
Class 
Book. 



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COPYRIGHT DEPOSIT. 



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HANDBOOK 



OF 



PHARMACOLOGY 



BY 

CHARLES WILSON GREENE 

A.B., A.M\, Ph.D.' 

PROFESSOR OF PHYSIOLOGY AND PHARMACOLOGY, UNIVERSITY OF MISSOURI ; MEMBER 
AMERICAN ASSOCIATION OF ANATOMISTS, AMERICAN PHYSIOLOGICAL SOCIETY, 
SOCIETY OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS; 
FELLOW OF THE AMERICAN ASSOCIATION FOR THE AD- 
VANCEMENT OF SCIENCE ; ASSOCIATE OF THE 
AMERICAN MEDICAL ASSOCIATION, 
ETC., ETC. 



WITH SEVENTY ILLUSTRATIONS. INCLUDING 
MANY NEW AND IN COLORS 



NEW YORK 

WILLIAM WOOD AND COMPANY 

MDCCCCXIV 



.Q-7 



Copyright, 1914 
By WILLIAM WOOD & COMPANY 



OCT 14 1914 



THE QUINN & BOOEN CO. PRESS 
RAHWAT, N. J. 

(U380862 



PREFACE 

The time has arrived in the differentiation of the teaching of 
medicine when the demarcation line should be more sharply drawn 
between those courses presenting to the student the scientific prin- 
ciples underlying the action of medicinal agencies and that phase of 
his training which deals with the practical use of medicaments in the 
alleviation of diseases. A parallel, illustrating the matter, can be 
drawn from the relations- of the subjects of Physiology and Pathology. 
Physiology undertakes to present the underlying principles govern- 
ing the reactions of the normal living body. Pathology deals with the 
reactions of the living body, but under conditions which we loosely 
classify as diseased, i.e., the reactions of the body when out of normal 
relations. Both treat of functions, but the two subjects are separated 
by the inherent nature which classifies one as normal functions, 
the other as pathological, a line which, of course, cannot be sharply 
drawn. Just so is it with the broad subject which deals with the 
reactions of the living body to drugs. The principles underlying this 
field are best presented from the standpoint of the reactions of the 
normal body to drugs and drug agents, which is the peculiar province 
of Pharmacology. The term Therapeutics, in the restricted sense, 
ought to apply only to that phase of the subject which deals with the 
reactions of the diseased body to drugs and drug agencies. These 
two phases of the broad field of Pharmacology and Therapeutics are, 
of course, intimately related, just as are Physiology and Pathology. 
And in the pedagogy of medical education they should be kept in their 
proper sequence, but should be presented in distinct and consecutive 
courses, as in the instance of Physiology and Pathology. Medical 
students should have placed in their hands a Textbook on Pharma- 
cology without being burdened and confused by a mass of matter 
on practical Materia Medica and Therapeutics while they are getting 
the principles of the subject of Pharmacology. 

The desire to carry forward this idea in meeting an organization 
which has already been well established in the medical curricula of 
our best schools has led to the presentation of this Textbook. 

Courses in Pharmacology have been organized along two lines: 
One represented by that splendid old Textbook on Therapeutics and 



PREFACE 



Pharmacology, by George B. Wood, which ran so many editions 
in the hands of his descendants. This is typical of the group which 
classifies the drugs primarily according to the physiological symp- 
toms they induce in the body. This classification, which characterizes 
a number of pharmacologies of the present, has in an introductory 
course the pedagogical disadvantage of presenting a confusing array 
of new facts to the student each time he shifts from one general 
topic to another. For example, under the chapter on Cardiac Stimu- 
lants, the student is suddenly brought face to face, not only with the 
great number of drugs, new and strange to him, which have this 
characteristic action on the cardiac apparatus, but he must correlate 
their actions throughout other parts of the body, making the problem 
doubly complicated. 

The other type of Textbook, of which Cushny's classical Phar- 
macology and Therapeutics is our best example, bases the organiza- 
tion on the twofold nature of pharmacological agencies, viz., the 
chemical relations of the drugs and the characteristic physiological 
reactions of particular groups. No method can be strictly logical in 
presenting such a wide range of facts without involving wasteful 
repetition. But Cushny 's method has the pedagogical advantage which 
may be illustrated by the subject of strychnine. Here the student 
is presented with the characteristic actions of a single new drug 
typical of a group. But he is asked to trace the reactions over the 
entire body with the physiology of which he is assumed to be familiar. 
In short, the student is asked to establish the scientific relations of 
a new substance or a group of substances within an organism with 
which physiology has already given him a working acquaintance. 

In gathering the material for this book, use has been made of 
the literature of physiology, pharmacology, and therapeutics to the 
extent called for in the presentation of the underlying principles of 
the subject. Recognizing that even the most elementary student 
often desires fuller detail of some phase of the subject, and that the 
teacher needs a ready reference to sources in the literature used to 
support given principles, a few references to original sources have 
been inserted as footnotes. The articles so referred to are, in the 
main, those which present reviews of the literature or through which 
the literature may become available. No attempt has been made to 
give exhaustive reference lists. Free use has been made of the stand- 
ard textbooks and encyclopedias of the subject, to the authors of 
which the writer expresses his particular obligation. 

It is hoped that the number of figures introduced from the litera- 



PREFACE v 

ture and from experiments in our own laboratories will be of special 
aid to both the student and the teacher. They are presented as 
standards for comparisons in laboratory experimental work as well as 
for the purpose of elucidating the subject matter of the text itself. 
For many of these illustrations I am especially indebted to my 
own students, to whom I here make grateful acknowledgment. 

Chas. W. Greexe. 
Columbia, Missouri. 

September 10, 1914. 



CONTENTS 

Chapter I.— GENERAL CONSIDERATION: PAGE 

Introduction and Definition — The Nature of the Action of Drugs — 
Relation of Pharmacological Action to Chemical Composition 
— Physiological Factors Modifying Pharmacological Responses — 
Nature of the Change Induced by Drugs in the Pharmacological 
Actions of the Body — The Method of Application of Drugs as 
Modifying the Changes in Pharmacological Activity — Changes 
Produced in the Reactive Power of the Individual by the Continued 
Application of the Drug — Summation and Tolerance — Pharma- 
cologic versus Therapeutic Action — The Fate of Drugs in the 
Body 1-18 

PART I. 

ORGANIC DRUGS. 

A. General Depressant Series. 

Chapter II.— THE ALCOHOL GROUP: 

Introductory and Chemical — Alcohol as a Local Irritant : on the skin ; 
on the mucous membrane of the mouth and stomach; the action 
of alcohol on the central nervous system; explanation of the nervous 
symptoms; action on the nervous system of lower animals; dura- 
tion of the effects on the central nervous system; action on the 
muscular tissue, on the heart and circulatory system, the respira- 
tory system, on the digestive tract; the liver in relation to alcohol 
oxidations; alcohol on metabolism; the elimination of alcohol; the 
effects of the repeated use of alcohol on the germ-plasm and fer- 
tility; alcohol habit and disease — Summary 19-38 

THE ANESTHETICS. 
THE ETHER-CHLOROFORM GROUP. 

Chapter III.— ETHER: 

Historical — Outline of the General Action of Ether: stages of anes- 
thetic effects — Details of the Action of Ether: on the central nerv- 
ous system, on the respiratory center, on the circulatory system and 
blood-pressure, on voluntary muscle, on the alimentary canal; the 
absorption, distribution, and execretion of ether — Summary . :}0-49 

Chapter IV.— CHLOROFORM: 

Details of the Action of Chloroform: stages of anesthetic effects: on 
the central nervous system, on the circulatory system, on the heari ; 
chloroform on the voluntary muscles, on the alimentary canal; tin- 
absorption of chloroform; the execretion of chloroform — Sum 
mary 50-57 

Chapter V.— NITROUS OXIDE: 

Historical and General — Nitrous Oxide on the General Activities of 

the Body — The Administration of Nitrous Oxide ... 58-62 

vii 



viii CONTENTS 

Chapter VI.— CHLORAL HYDRATE: PAGE 

Historical and Chemical — Pharmacological Action : the general symp- 
toms; chloral hydrate on the nervous system 63-65 

Chapter VII.— MORPHINE AND THE OPIUM SERIES: 

Historical and Chemical — Outline of Pharmacological Action — Details 
of Action: on the central nervous system, the circulatory system; 
reactions of the heart and its nervous mechanism; normal move- 
ments of the stomach and of the intestine; action of morphine on 
the stomach and intestine; morphine on the eye, on the frog; 
morphine on metabolism — Action of Codeine, Papaverine, Thebaine, 
and Heroin — Excretion of the Morphine Group — The Abuse of 
Opium — Summary 66-83 

Chapter VIII.— APOMORPHINE AND APOCODEINE: 

Historical and Chemical — Outline of Action — Details of Action : on 
the central nervous system; depressant action on muscular tissue; 
apocodeine on nervous structures, on the alimentary canal and 
urinary motor system; apocodeine in support of pharmacological 
investigation — Irritant Emetics 84-88 

B. General Stimulating Series. 

Chapter IX.— THE CAFFEINE GROUP: 

Historical and Chemical — Outline of Pharmacological Effects — Details 
of effects of caffeine: on the central nervous system, the spinal 
cord, the medulla; action on skeletal muscle, on the circulation: 
the cardiac mechanism; the vasomotor apparatus; on the respira- 
tory mechanism; caffeine on metabolism; diuretic action; absorp- 
tion and excretion — Summary 89-95 

Chapter X.— THE STRYCHNINE GROUP: 

Chemical and Historical — Outline of Action — Details of Action: on 
the spinal cord, the medulla, on respiration, on the circulation, on 
skeletal muscle; action on the special sense organs, on the ali- 
mentary canal, on metabolism; excretion — Strychnine Poisoning — 
Brucine — Summary 96-106 

C. Drugs with Specific Action for Peripheral Parts of the Xcrrous System. 

Chapter XI.— THE CURARE GROUP: 

Historical and Chemical — Outline of Action — Details of Action: on 
the motor nerve endings, on peripheral ganglia; absorption from 
the stomach — Comparison with Related Drugs .... 107-111 

Chapter XII.— THE ATROPINE SERIES: 

Historical and Chemical — Outline of Pharmacological Action — Details 
of Action: general symptoms; action on the central nervous system: 
specific action on the eye; specific action on glands, on the circula- 
tory system, on the alimentary canal, the stomach, and the in- 
testine, on the bladder and uro-genital apparatus; excretion — Sum- 
mary 112-121 



CONTEXTS ix 

Chapter XIII.— THE PILOCARPINE, MUSCARINE, PHYSOSTIG- 
MINE GROUP: 

I. PILOCARPIXE. pAGE 

Historical and Chemical — Outline of Action — Details of Pharmacolog- 
ical Action : on glands, on the circulatory apparatus, the heart, 
the blood-vessels, on the respiratory tract, on the central nervous 
system, the alimentary tract; action of pilocarpine on the iris 
and the ciliary mechanism of the eye — Summary. 

II. MUSCARINE. 

Historical and Chemical — Outline of Action — Details of Action : on 
the heart and circulatory system, on blood-pressure, on the glands 
and the alimentary tract, on the eye. 

III. PHYSOSTIGMIXE OP ESERINE. 

Historical and Chemical — Outline of Pharmacological Action — Details 
of Action: on the eye, on the circulatory apparatus, on striped 
muscle; physostigmine on the muscles of the stomach and intes- 
tines, on the central nervous system — Summary: comparison of 
the pilocarpine group 122-135 

Chapter XIV.— THE NICOTINE SERIES: 

Historical and Chemical — Outline of Pharmacological Action — Details 
of Pharmacological Symptoms — Action: on the central nervous 
system, the cerebral cortex and medulla, the spinal cord; nicotine 
on peripheral ganglia, on the circulatory system, on cardiac muscle; 
the local nervous apparatus of the heart; the vasomotor system; on 
the glandular apparatus; the action of nicotine on the eye, on the 
alimentary canal; excretion — The Xicotine Habit: tolerance . 136-146 

Chapter XV.— THE CONIINE, SPARTEINE GROUP: 

I. CONIINE. 

Historical and Chemical — Outline of Action — Action: on the central 
nervous system, on the autonomic nervous system, on voluntary 
motor nerve endings, on the circulatory apparatus, on the respira- 
tor}* movements; excretion of coniine. 

II. PYRIDINE AXD PIPERID1XE; III. LOBELINE; IV. GELSEM- 
IXIXE; V. SPARTEINE ... 147-151 

Chapter XVI.— EPINEPHRINE: 

Historical and Chemical — Outline of Pharmacological Action — Details 
of Action: on the nervous system: epinephrine on blood-pressure, 
on the heart, the salivary glands, on gastric and intestinal move- 
ments, on the eve; adrenaline on the urogenital apparatus, on the 

eye; glycosuria — General Discussion of Epinephrine — Sum- 
mary 152-164 

Chapter XVII.— THE ERGOT SERIES: 

Eistorical and Chemical — Outline of Action — Details of Pharmacolog- 
ical Action of chemically pure principles; ergotoxine; isoamyla- 
mine; parahydroxy phenylethylamine ; extracts of ergot; ergol on 
the uterus, on the circulatory Bystem. the heart, on the alimentary 
canal; effect of ergot on other physiological mechanisms . 166 17:> 



x CONTENTS 

D. Drugs with Primary Activity on Smooth Muscle. 

Chapter XVIII.— BARIUM CHLORIDE: PAGE 

Outline of Pharmacological Action — Action: on the circulatory system, 
on the heart, on the peripheral arterioles, on other smooth muscle, 
skeletal muscle, the central nervous system; local action of barium 
salts; therapeutic indications 174-177 

Chapter XIX.— THE NITRITES AND THE NITRO-GLYCERINES: 

Chemical — Outline of Action — Action : on the circulatory system, the 
heart, on the respiratory apparatus ; formation of methemoglobin — 
Summary 178-180 

E. Glucosides of the Digitalis Series. 

Chapter XX.— THE DIGITALIS GROUP: 

Historical and Chemical — Outline of Action — Details of Action: on 
the circulatory system, the heart, on the peripheral arterioles; 
digitalis on the central nervous axis, as a diuretic; local irritating 
effect — Cumulative Action — Summary. 

Bufonine and Buf otaline — Chemical — Action : on the frog's heart, on 

the mammal, on blood-pressure and the pulse .... 181-104 

Chapter XXI.— THE SAPONIN AND SAPOTOXIN GROUP: 

Historical and Chemical — Sapotoxin: as an irritant; toxic systemic 

effects; general saponin symptoms; solanin 195-196 

F. Drugs, Chiefly Alkaloids, that Primarily Influence General Metabolism. 

Chapter XXIL— HYDROCYANIC ACID: 

Chemical — Outline of Action — Details of Action: on the central 
nervous system, on respiration, the circulatory system; metabo- 
lism 197-200 

Chapter XXIII.— ACONITE: 

Historical and Chemical — Outline of Action: the systemic action; 
aconite on the central nervous system, the circulatory system, the 
blood-vessels, on the glands, as an antipyretic . . . 201-205 

Chapter XXIV.— VERATRINE: 

Historical and Chemical — Outline of Pharmacological Action: vera- 
trine on sensory and nervous mechanisms, on skeletal muscle, heart 
muscle, smooth muscle 206-209 



Chapter XXV.— COLCHICINE: 

Chemical: general systemic and toxic effects; colchicine on the white 

blood corpuscles 210-211 

Chapter XXVI.— EMETINE: 

Chemical — Details of Action — Systemic Actions 212 



COXTEXTS xi 

G. Drugs Poisonous to General Protoplasm. 

Chapter XXVIL— COCAINE: PAGE 

Historical and Chemical — Outline of Pharmacological Action — x^ction : 
on the central nervous system; cocaine on the circulatory system, 
the peripheral blood-vessels, on the heart, on skeletal muscle; 
cocaine on the eye; elimination of cocaine; local and anesthetic 
action; the cocaine habit — Substances which produce anesthesia 
similar to cocaine: tropacocaine, eucaine, stovaine, holocaine, 
novocaine — Summary 213-221 

Chapter XXVIII.— QUININE: 

Historical and Chemical — Outline of Action — Details of Systemic 
Action: action on undifferentiated protoplasm; quinine as an anti- 
pyretic; action on muscle, on the digestive tract and digestion, 
the liver, the central nervous system ; elimination of quinine — 
Summary 222-230 

H. The Coal Tar Series. 
A. 
Chapter XXIX.— THE COAL TAR ANTIPYRETICS: 

Historical and Chemical: the general antipyretic action; action of the 
antipyretics on the central nervous system, on the circulation; 
variations in susceptibility; comparison of acetanilide, antipyrine, 
and acetphenetidine 231-236 

B. 

Chapter XXX.— THE COAL TAR ANTISEPTICS: 

Historical and Chemical — Outline of Pharmacological Action of the 
Coal Tar Antiseptics. 

I. THE PHENOLS. 

Toxicity to protoplasm: on the central nervous system, the circulatory 
system; the excretion of carbolic acid; toxicology; summary. 

II. SALICYLIC ACID AND THE SALICYLATES. 

Toxicity to general protoplasm; action on the central nervous system, 
on the circulatory system, on the alimentary canal; antipyretic 
action; acetyl-salicylic acid; summary 237-247 

I. Internal Secretions. 

Chapter XXXI.— THE THYROIDS AND PARATHYROIDS: 

General Introduction — Internal Secretions of the Thyroid and Para- 
thyroid Glands. 

A.— THE THYROID AND THYROIODIN. 

Historical and Chemical — Outline of Action: effects of the removal 
of the thyroids; engrafting of thyroid and parathyroid tissue; 
interrelationship of the thyroids and the parathyroids; feeding 
of the thyroid tissue and of thyroiodin. 

B.— PARATHYROIDS. 

Systemic phenomena following removal of parathyroids; metabolism 
after parathyroidectomy; theoretical 24 



xii CONTENTS 

Chapter XXXII.— THE PITUITARY GLAND AND THE HYPOPH- 

YSIS: PAGE 

Anatomical — Outline of Pharmacological Action — Details of Pharma- 
cological Action. 

A.— PITUITARY GLAND. 

Changes in metabolism following removal of the pituitary; administra- 
tion of pituitary; clinical evidences from atrophy and hypertrophy 
of the pituitary; interrelation of the pituitary and other organs.' 

B.— HYPOPHYSIS. 

Influence of the hypophysis on the functions of nerve structures, the 

heart, on smooth muscular structures; hypophysin . . . 255-258 

J. Irritants and Counter Irritants. 
General Introduction. 

Chapter XXXIIL— THE BACTERIAL TOXINS: 

Historical and Introductory: nature of the irritant action; the inflam- 
matory process a physiological response to irritant action; action 
of bacteria and bacterial toxins; characteristics of toxins; type of 
toxin action; antitoxins; specificity of toxins .... 259-267 

Chapter XXXIV.— IRRITANTS OF THE EXTERNAL SKIN: 

Introductory — Outline of Action : permeability of the skin to certain 
irritants; acute inflammation; action of the volatile oils; toxic 
glucosides of the mustard series; cantharidin .... 26S-273 

Chapter XXXV.— THE VEGETABLE CATHARTICS. IRRITANTS 
AFFECTING THE ALIMENTARY CANAL: 

Introduction — Outline of Pharmacological Action : nature of the 
reaction by which the vegetable purgatives produce catharsis; 
action at the point of contact; action after absorption; the 
anthracene group; the jalap group; the neutral oil series . . 274-281 

Chapter XXXVI.— COUNTER IRRITANTS AND THE PHENOM- 
ENON OF COUNTER IRRITATION: 

The theory of counter irritation; conditions which suppress counter 
irritation; the practical application of counter irritants; counter 
irritant agents 282-287 

PART II. 

INORGANIC DRUGS. 

K. Drugs Characterized to Greater or Less Extent hi/ Salt Action. 

Chapter XXXVII.— UNDERLYING PRINCIPLES OF SALT ACTION: 

Underlying Principles of Salt Action — Genera] Considerations of the 
Physical and Chemical Characteristics oi Salts in Solution — 
Crystalloids and colloids; dissociation; electrolytes-, freezing poinl 
depression; osmotic pressure and osmosis .... 

Chapter XXXVIII.— WATER: 

Action of distilled water on isolated tissues; drinking water; mineral 

waters; the influence of water on metabolism and on the kidney 294-296 



CONTENTS xiii 

Chapter XXXIX.— ISOTONIC PHYSIOLOGICAL SOLUTIONS: PAGE 

Physiological saline; perfusions of physiological salines; Ringer's solu- 
tion; Locke's solution; sera and lymphs; summary . . . 297-303 

L. Detailed Action of Salts Normal to the Body Pluids and of Their Chemical 

Relatives. 

Chapter XL.— THE SODIUM-POTASSIUM GROUP, INCLUDING 
THE CHLORIDES, BROMIDES, IODIDES, SULPHATES, NI- 
TRATES, ETC.: 

The Sodium Salts: sodium chloride, the bromides, iodides, sodium 
nitrate, sodium sulphate, sodium phosphate — Potassium Salts — 
Ammonium Salts: on secretion; on the nervous system; excretion 
— Lithium, Rubidium, and Cesium Salts 304-309 

Chapter XLL— THE SALTS OF THE CALCIUM-MAGNESIUM 
GROUP, IN COMBINATION WITH VARIOUS ANIONS: 

Calcium Salts: in relation to the heart; in the coagulation of blood; 
on nerve tissue; on metabolism; excretion — Magnesium Salts — 
Barium and Strontium 310-314 

Chapter XLIL— THE SALINE CATHARTICS: 

Nature of the Action of the Saline Cathartics: sodium sulphate; 
sodium potassium tartrate; magnetism sulphate; the saline 
cathartics as enemas 315-323 

Chapter XLIII.— ALKALIS AND ACIDS: 

Alkalis: the cauterizing action of the alkalis; the physiological action 

of the alkalis — Acids: the action of dilute acids .... 324-328 

Chapter XLIV.— OXIDIZING AGENTS, OXYGEN, PEROXIDE, ETC.: 

Oxygen : effects of increase of oxygen — The Peroxides . . . 329-332 

Chapter XLV.— THE SALTS OF THE HEAVY METALS: 

The general reactions of salts of heavy metals; absorption of salts of 
heavy metals; distribution and excretion of the heavy metals in the body 333-337 

Chapter XLVL— IRON: 

The normal relations of iron in the body; absorption of iron; iron- 
protein compounds; astringent action 338-340 

Chapter XLVIL— SULPHUR AND THE SULPHUR COMPOUNDS: 

Action of sulphur, sulphides, sulphates; the organic sulphur com- 
pounds 341-342 

Chapter XLVIII.— PHOSPHORUS AND THE PHOSPHORUS COM- 
POUNDS: 

Historical — Outline of Pharmacological Action — Action: <»t' phos- 
phorus as a genera] protoplasmic poison; fatly degeneration after 
phosphorus poisoning; action on the skeletal structures; the in- 
organic phosphates; organic phosphorus compounds . 343-349 



xiv CONTENTS 

Chapter XLIX.— ARSENIC AND ANTIMONY: PAGE 

A. Absenic. — Introductory — Outline of Action: general toxicity of 

arsenic compounds; on the circulatory system; arsenic on the 
alimentary tract; metabolism; excretion of arsenic — Organic and 
Synthetic Arsenic Compounds: the arsanilates; salvarsan. 

B. Antimony. — The irritant action of antimony 350-356 

Chapter L.— LEAD SALTS: 

Historical and Chemical — Outline of Action: the general toxic action 
of lead salts; chronic lead poisoning; lead on the digestive tract; 
excretion of the lead by glands; excretion of lead by the kidneys: 
reaction on the circulatory system, on the nervous system; mus- 
cular effect 357-363 

Chapter LL— ZINC SALTS: 

General toxic and disinfectant action of copper salts; the local action; 

the systemic action of zinc 364-365 

Chapter LIL— THE SALTS OF COPPER: 

General toxic and disinfectant action of copper salts; systemic action 

of copper; the elimination of copper salts 366-367 

Chapter LIIL— THE MERCURY SALTS: 

Chemical — Outline of Pharmacological Action — Details of Action: 
the absorption of mercury; action on bacteria, on differentiated 
animal protoplasm, on the alimentary tract, on the central nervous 
system, on the circulatory and respiratory systems; mercury on 
the kidney; excretion of mercury; chronic poisoning . . . 368-375 

Chapter LIV.— SALTS OF SILVER: 

The local and antiseptic action of silver salts; the toxic action; sys- 
temic effects "376-377 

Chapter LV.— SALTS OF BISMUTH: 

The action of soluble bismuth compounds; the action of insoluble 

bismuth salts 378-380 

APPENDIX 381-386 



CHAPTER I. 

PHARMACOLOGICAL FACTORS OF GENERAL 

BEARING 



Introduction. 

Pharmacology is the science which treats of changes in the 
physiological actions of normal living organisms induced by chemical 
or physical-chemical agencies. It must be understood that the word 
has often received a wider range of application in the literature, 
especially by the older writers. The term Pharmacology has been 
used synonymously with the term Materia Medica in its broader 
sense, also to designate the broad field of actions induced in patho- 
logical as well as in normal organisms. The present tendency in 
these days of specialization is to restrict the boundary of the field. 
In this book the term pharmacology is used in the restricted sense 
expressed by the definition just given. 

Pharmacology, from this point of view, is not limited by any 
question of utility or application in the art of healing. It is quite 
immaterial whether a given agency be destructive of life, or of aid 
in maintaining life. If the agency is one that primarily influences the 
otherwise normal physiological processes, inducing reactions that are 
characteristic and constant, then it belongs to the field of phar- 
macology. 

No sharp and all-inclusive boundary can be set around pharma- 
cological agencies. Schmiedeberg has given a classical definition in 
which he specifically excludes substances capable of assimilation. 
Yet many recognized food materials have a decided influence on the 
normal reactions of the living body. They may be primarily nutritive, 
yet at the same time they produce changes in the physiological func- 
tions over and above those of simple nutrition, hence to that extent 
are pharmacological in nature. Also, many chemical agencies, which 
are well recognized as of the pharmacological group, for example 
alcohol or strychnine, are oxidized in the body and thus yield energy, 
and are to that extent nutritive, therefore foods. Nutritive processes 
and those of the type indicated as pharmacological shade from the 
one to the other so that no sharp dividing line can be drawn. 



2 PHARMACOLOGICAL FACTORS 

Pharmacological agencies are, for the chief part, chemicals, i.e., 
drugs. Many of these chemicals are of practical value in disease. 
The art of the application of drugs in the modification of the processes 
of disease with the purpose of recovering the normal functions is 
known as therapeutics. This term also is used with widely varying 
meanings by different writers. Occasionally the word therapeutics 
is given the meaning which includes pharmacology as outlined above 
and vice versa. The term drugs should be restricted to designate 
chemicals of therapeutic value. In the restricted interpretation of 
the relations of this field pharmacology deals with the physiological 
action of chemicals on the normal body while therapeutics deals 
with the action of drugs on the diseased body. In therapeutics chemi- 
cal agencies are used for the purpose of recovering the normal, i.e., 
in the art of healing. In pharmacology, on the other hand, the whole 
intent of investigations and procedures is for the scientific purpose 
of unfolding the reactions induced. That the net results of pharma- 
cological investigation may or may not yield a body of facts of 
positive utility is wholly a secondary consideration, though in 
presenting the subject from the standpoint of the undergraduate 
medical student it is the commendable practice to choose those 
materials and drugs which are of most importance in the practice of 
the art of healing. 

If the action of the drug is destructive of the living organism it 
is said to be a poison. The science which deals with the limited 
field of drugs with poisonous action is termed toxicology. It is a 
subdivision of pharmacology. 

Formerly much attention was given to the source and preparation 
of drugs. These subjects are now of primary interest, chiefly to the 
manufacturer and professional pharmacist. The present tendency 
is to eliminate them from other than secondary consideration under 
the subject of pharmacology. However, the definitions and limita- 
tions of these subjects may be given here for the sake of a fuller 
understanding of the general field. Materia Medica deals with the 
origin, preparation, and composition of drugs. As many of the active 
drugs are derived from plant tissues, the special field of the study 
of drug-producing plants is recognized under the title pharmacognosy. 
The art of preparing and compounding drugs is known as pharmacy. 
and the skilled druggist who does the compounding is called the 
pharmacist. With the present great development in the manufacture 
and preparation of drugs and drug principles we arc rapidly dispens- 



NATURE OF THE ACTIOX OF DRUGS 3 

ing with the services of the pharmacist, who formerly played so large 
and important a part in the preparation of medicinal agencies. 

A study of pharmacology assumes a wide and intimate knowledge 
of the subject of physiology. It is only on the basis of such knowl- 
edge that one can build the science of pharmacology. Physiology 
deals with the intricate and complicated reactions of the living body 
to every change either in the internal or external environment. These 
changes are constantly shifting throughout the life cycle of the 
individual organism and these shifting reactions make up the sum 
total of the physiological life itself. When pharmacological agencies 
are introduced into the body or brought into contact with living 
protoplasm by whatever device, the living tissue or organism responds 
to their presence. In other words, the presence of the special agency 
is only one of the numerous factors which induce response in the 
living protoplasm. The study of drug action is, therefore, only a 
restricted portion of the field of physiology. 

Modern science has taken up the questions of pharmacology with 
the same vigor and spirit of investigation which has characterized 
the development of physiological knowledge during the last three- 
quarters of a century. In this spirit scientists have studied the 
details of the changes induced by drugs, thus establishing the facts 
on a strictly scientific observational basis. This method and the re- 
sults are in direct opposition to the old empiricism. The findings 
have been seized upon by the clinician and therapeutist, since they 
enable him to proceed in the light of definite and known pharmaco- 
logical actions of the agent. On the assumption that a given 
drug, which has been proved to induce a change of a certain nature 
in the normal organism will induce a change in the same direction 
in the diseased or pathological organism, the clinician can apply a 
given drug with a definite knowledge of what effects may be expected. 
This is the rational treatment in opposition to the empirical. Modern 
medicine and modern therapeutics look to the science of pharmacology 
for the basic facts for a rational procedure. 

II. 

The Nature of the Action of Drugs. 

The chemical substances that produce pharmacological reactions 
in the body by virtue of chemical combinations with constituents of 
the body are properly called drugs. The term is an old and con- 



4 PHARMACOLOGICAL FACTORS 

venient one, though its application is often vague and indefinite. 
The character of the change in the reactions depends upon many 
environmental conditions, of which one of the most important is 
the manner in which the drug is brought into contact with the tissues 
of the organism. On this basis the drug actions may be either local 
or general. 

i. Local actions. — A certain class of changes produced in the 
body by drugs is dependent upon the fact that the chemical is 
brought into contact with only a restricted part of the body, hence 
the restricted action is purely local and for purely mechanical reasons. 
For example, if strong sulphuric acid comes in contact with the skin 
it will produce chemical destruction of the tissue of that local spot. 
While sulphuric acid is generally destructive to protoplasm, in this 
instance it can act only locally in the same sense that a hot piece of 
iron will sear only that portion of the body which it touches. 

2. General actions. — On the other hand, when chemical agents 
are introduced into the body in such manner that they are distributed 
throughout its extent by means of the circulation, then the reactions 
that occur are characterized by two general types. 

The drug may be one capable of inducing change in the physio- 
logical activities of the body whatever the nature and function of 
the organs or parts considered. If so, it is said to have a general 
action. An example is found in alcohol. "When alcohol is absorbed 
into the circulation and distributed throughout the organism it in- 
duces a change in function in all parts of the body. 

Most of the drugs used in practical medicine belong to this 
class. It cannot be said that the chemicals produce exactly the 
same change in every type of protoplasm, yet the parts of the body 
affected are so numerous and widely distributed that the general 
functions are thrown out of balance, hence the action of the drug is 
said to be general in its nature. The majority of the physical-chemical 
changes induced in the body are of this class, especially the purer 
examples of salt action. 

3. Specific actions. — In sharp contrast with these drugs of general 
action is a different class, namely, the specific drugs. In this class, 
although the drug may be brought in contact with all the tissues of 
the body still it shows especial affinity for certain tissues only and 
not for others. Nicotine is an example of such a drug. This alkaloid 
picks out especially the nervous tissue. Its specific action is still 
more detailed in that it forms compounds with that differentiation 
in nerve tissue represented by the link between the pro- and post- 



NATURE OF THE ACTION OF DRUGS 5 

ganglionic neurons of the autonomic system. While nicotine does 
enter into reaction to some extent with other portions of the nervous 
tissue and with the muscular tissues, still the intensity of the action 
is so much stronger at the particular sjmapsis that the other reactions 
are overshadowed, thrown into the background as it were. Hence 
this nicotine reaction is said to be specific. Numerous illustrations of 
this action can be given. Pilocarpine, acting at the same point, would 
be antagonistic to atropine, the characteristic curare action on periph- 
eral motor nerve endings, the action of strychnine on certain synapses 
in the central nerve axis, and of caffeine on muscle and on nerve, 
particularly the nerve structures of the higher centers are examples. 
The behavior of such drugs in the body is always in sharp contrast 
with those reacting generally throughout the body such as the general 
protoplasmic poisons. The latter class are characterized by the 
changes which they induce in the physiological responses of general, 
i.e., undifferentiated, protoplasm. The specific drugs are characterized 
by the selective action on highly differentiated points in the structure 
of the animal body. 

4. Indirect action of drugs. — Drugs also induce many changes 
in the normal functions of the body as indirect actions. That is to 
say, as a result of the primary action of the drug in the body the 
balance that exists among the coordinated physiological mechanisms 
is upset, hence there will follow a chain of effects induced by the 
shifting in the function of that tissue especially influenced by the 
drug. These purely secondary effects are physiological rather than 
pharmacological. Nevertheless they must be understood by the phar- 
macologist, and especially by the therapeutist who makes a rational 
application of the drug in disease. A simple illustration of this kind 
of secondary effect is found in the change of the heart rate produced 
by atropine. This drug paralyzes the endings of the vagus in the 
heart, thus eliminating the tonic control of the vagus. As a result 
the heart rate is greatly increased, not due to any direct effect of the 
drug, but purely secondary to the action of the drug in eliminating 
the inhibitory function of the vagus nerve. In like manner many 
drugs which produce profound changes in the circulatory system are 
accompanied by secondary effects on the respiratory mechanism or the 
renal system. Most so-called " tonics " induce their favorable changes 
in nutrition and metabolism in a purely indirect or secondary way. 



6 PHARMACOLOGICAL FACTORS 

III. 

Relation of Pharmacological Action to Chemical Composition. 

When drugs are introduced into the body they produce changes 
that are in nature either physical-chemical or chemical. In either 
case the type of reaction will depend in large measure upon the 
chemical composition of the drug itself. If the drug is of such 
chemical nature as to produce only physical changes, such as changes 
in osmotic pressure, etc., then its influence on the physiological be- 
havior of the organism will be limited to the class of phenomena 
characterized by a disturbance in surface tension, osmotic equilibrium, 
etc. If, on the other hand, the chemical nature of the drug is such 
as will react with the protoplasmic constituents to form new or 
unusual chemical compounds, then the reactive power of the proto- 
plasm will be altered, owing to the change in the chemical composition 
of the protoplasm itself. 

Physical-chemical changes in the body may be induced in a num- 
ber of ways, for example the digestive enzymes acting upon the food 
in the normal process of digestion produce hydrolytic changes in 
which there is an increase in the molecular concentration in the digest- 
ing mass. This condition alters the osmotic equilibrium as between 
the digesting food and the lining tissue of the alimentary tract. The 
physical result is an enormous increase in the interchange of par- 
ticles as between these two substances, i.e., the foods and the mucous 
membrane. The cleavage products of the food will pass into the 
alimentary epithelial lining in relatively large numbers constituting 
the process of absorption. If, however, the content of the alimentary 
tract consists of such substances as magnesium sulphate which readily 
go into solution, but which permeate the lining cells with difficulty, 
then the osmotic balance will result in the passage of large quantities 
of water into the alimentary tract, thus greatly increasing the total 
mass and its fluidity. Such actions are purely physical-chemical. 

Chemical changes, especially in those drugs that act specifically 
on the protoplasm of the organism depend upon a chemical reaction 
between the drug and some portion of the protoplasm of the living 
tissue. The chemical composition of some of the drugs has not yet 
been determined, but the greater number of pharmacological agents 
have well-known chemical composition. On the other hand, the exact 
and detailed chemical composition of the protoplasm of the tissues 
of the body is not known. There are many physiological indications 
of a high degree of involved and complex differentiation between the 



FACTORS MODIFYING RESPONSES 7 

tissues. These are indicated by the numerous cytological methods of 
staining, as well as by the details of variation in phenomena of physio- 
logical reaction. But rarely can one specify what is the particular 
chemical nature of a given differentiated portion of the living body by 
virtue of which it is capable of executing its characteristic functions. 
Nevertheless, we do not doubt that drugs induce changes in physio- 
logical reaction by a process of chemical reaction. Ehrlich has ad- 
vanced a widely accepted hypothesis in accounting for the specific 
effect of toxines and anti-toxines. He and his followers have de- 
veloped an elaborate artificial scheme to explain the type of reaction 
of substances of this class. Many different groups of drug actions 
can be explained along similar grounds, namely, on the assumption 
that some radical in the protoplasm combines with the drug or some 
portion of the drug. The new compound changes the nature of the 
protoplasm with the result that its physiological possibilities are 
altered. 

IV. 
Physiological Factors Modifying Pharmacological Responses. 

It is evident that the reactions produced by a drug in the body 
do not depend altogether upon the chemical nature of the drug. 
The structure of the protoplasm in an animal, especially in the 
higher mammals, is more complex from the standpoint of chemical 
structure than any known drug. One only has to consider for illus- 
tration the enormous differentiations among animal species, differ- 
entiations which are slight from the individual point of view, but 
collectively are sufficient to give the characteristic specific qualities. 

In a similar manner the individuals of the species or races of man 
himself owe their individual characteristics to variations in proto- 
plasmic composition throughout the body. These variations are most 
obviously expressed through morphological characters, but a closer 
analysis shows that a morphological differentiation is only the machin- 
ery for an even more subtle physiological differentiation. Even from 
this broad point of view it is obvious that the responses which one 
individual will give to a drug are not, in fact cannot be exactly 
duplicated in another. The details of this phase of the subject can 
better be appreciated by considering specific factors. 

i. Age of the protoplasm. — Of all the physiological character- 
istics influencing the pharmacological reaction of protoplasm age is 
one of the most important, second only perhaps to that of species. A 
young individual possesses different capability from the adult, whether 



8 PHARMACOLOGICAL FACTORS 

we make the application to man or to species of lower animals. If one 
considers a child, for example, at the time say of birth, there are 
several factors of which the following are important. First of all 
the differentiations of the body are incomplete at this stage, therefore 
the interrelations of pharmacological responses are not to be too 
strictly compared with those of an adult. Detailed changes in sus- 
ceptibility of the central nervous system to recognized stimulation, 
such as characterize the adult, cannot be wholly reproduced at this 
age, hence the detailed variations in responses induced by a drug 
such as caffeine vary widely from those induced in the adult, a varia- 
tion which may be compared qualitatively with the differences in 
response. An even more important factor is found in the greater 
susceptibility of young protoplasm to biological change in character 
as between adult man and the lower animals. Classical experiments 
in biological fields in recent years have fully emphasized the fact that 
young protoplasm is strongly imbued with the " impulse to growth." 
This characteristic overshadows the dynamic processes of adult proto- 
plasm. Keactions of the young are to that extent different in nature. 
It is obvious that the responses to special conditions such as an 
environment of drugs will to such extent be fundamentally modified. 
Among other things young protoplasm is quantitatively, i.e., 
weight for weight, much more susceptible to drug action. In perform- 
ing experiments on animals or in the practical use of drugs in thera- 
peutics this fact has long received recognition. In dose tables allow- 
ance has to be made, not only for the smaller proportionate size of 
the young in comparison with the adult in computing the adequate 
dosage (which is always figured for the adult), but for the difference 
in susceptibility of the child in comparison with the adult. Physi- 
cians in practical therapeutics have undertaken to express this rela- 
tion in formulae for computing the dosage for children which shall 
take into account both age and weight. Young's formula, which is 
widely used and is sufficiently accurate for all practical purposes, 
computes the dosage for a child as follows: The fraction obtained 
by dividing the age of the child by the age plus twelve gives the 
proper part of the adult dose to be given, i.e. : 

ntro 

Young's formula,=The adult dose X — ^r 

age + 12. 

A year-old child would receive,- •* . y A — jg of the adult dose, or a 

4 1 

four-year old child . , , n =-r the adult dose. 

4 + 12 4 



FACTORS MODIFYING RESPONSES 9 

Children under one year, i.e., infants, must receive even smaller 
proportionate doses. Fried 's rule, applying to this age, is: The dose 
for the adult X the age in months -s- 150. 

Age susceptibility cannot always be figured in terms of formulae. 
It is well known that young children are peculiarly susceptible to 
certain particular drugs. These can only be known through the 
process of experience. 

2. Race and species differentiations. — As it is with age suscepti- 
bility so is it with species or race susceptibility. The very foundation 
of specific or race variation either in man or animals is expressive 
of protoplasm deviation in composition of a nature which leads to 
dissimilar responses to chemical agencies. Although many of our 
pharmacological tests are made on the common house animals, the 
cat and the dog, it is well known that these two animals give quite 
different responses to certain particular drugs, for example morphine. 
When weight and age and other individual characteristics are taken 
into account still there remains this qualitative difference, which is 
racial or due to species. The same type of variation is met with in 
the different races of man. The colored race, for example, is more 
susceptible to certain types of toxemia than the white, and vice 
versa. 

3. Individual susceptibility among both man and animals. — A 
wide range of individual susceptibility to drugs has been noted. Some 
individuals are especially responsive to certain particular drugs. 
For example, now and then will be found a person who is peculiarly 
responsive to the alkaloid strychnine. Even the small quantity of 
this drug customarily given in the form of a tonic to the average 
individual, will be sufficient to produce incipient tetany in a highly 
susceptible individual. This characteristic rests on some form of 
differentiation in the protoplasm. It is met with in common experi- 
ence in the fact that one individual may be unable to take milk in his 
food, another strawberries, or honey, etc. 

The opposite of this type of variation is found in individual 
tolerance. Great variations are found in the ability of individuals 
to throw off the particular action of certain drugs. In common ex- 
perience the most widely known of these reactions is that of tolerance 
to alcohol and to nicotine. While certain individuals are intoxicated 
by minute quantities of alcoholic beverages others can take relatively 
large quantities without marked evil effects. The particular cause of 
these variations among individuals cannot now be stated as it still 
belongs in the realm of the unknown, and for that reason we are in 



10 PHARMACOLOGICAL FACTORS 

position to give it a special name, namely idiosyncrasy. This type of 
variation, however, rests on an inherent variation in the nature of 
the tissues of the individual concerned. The term idiosyncrasy is 
not used to express that type of susceptibility or of tolerance which 
is acquired by repeated experience. 

4. Sex susceptibility. — Sex characteristics are generally stated to 
be a factor influencing susceptibility to the action of drugs. Though 
not always admitted, it is currently stated that women require smaller 
doses of therapeutic agents than do men of equal size. This differ- 
entiation is, doubtless, to some extent, the same in character as that 
represented by species differences, though they are more specifically 
physiological. The physiological life of women is subject to periodic 
disturbances in poise and under these particular conditions there is 
often a greater response in the reaction to particular drugs. In the 
nervous system, in the glandular system, and especially in the uro- 
genital system which is correlated particularly with the sex develop- 
ment, we have differences which influence the quantitative reaction of 
drugs. The more subtle sex differences which have long been recog- 
nized probably rest not so much on mass differences as on the variations 
in correlation between the organs of the general bodily functions 
as influenced by the primary sex organs, chiefly through their in- 
ternal secretions. 

In pregnancy there is a very great disturbance of physiological 
equilibrium. The usual coordinations are thrown far out of balance 
by the physiological adjustments to the developing fetus and the 
enlarging uterus. The nerve reflexes are more delicately poised and 
are stimulated into action by less profound changes in the environ- 
ment than usual. The responses to pharmacological agents are for 
these reasons greater. Drugs also pass from the mother to the de- 
veloping child, whose tissues are more susceptible. A non-toxic con- 
centration for the tissues of the mother may prove fatal to the child. 
The child in the uterus may also be profoundly affected by the sec- 
ondary changes in its nutritive condition, superinduced by the 
primary responses of the respiratory or circulatory sj-stems of the 
mother, for example in surgical anesthesia. 

Preceding and during the menstrual period there is great dis- 
turbance in the interrelations of the physiological reaction. Drugs 
displayed at this time produce effects somewhat differently co- 
ordinated in comparison to the effects ordinarily and normally called 
forth. The state of the body is comparable to that under many con- 
ditions of disease and the question of reaction variation is essentially 



CHANGE INDUCED BY DRUGS 11 

one of practical therapeutics. During that crisis in the life of a 
woman known as the menopause there are somewhat similar physio- 
logical disturbances that need to be taken account of in the interpre- 
tation of pharmacological reactions. 

5. The influence of mass, i.e., proportionate weight of active 
tissue. — In the display of drugs in the human body it is found that, 
other things being equal, there is a response proportionate to the 
mass of active protoplasm involved. Two individuals of similar type 
and build, but of dissimilar weights require dosages proportionate 
to their weight, if equivalent responses are expected. However, weight 
in itself is not a sufficient guide. Adipose tissue is inactive tissue, 
hence variation in weight due primarily to adipose tissue must not be 
taken into account in determining dosage. It is only the active proto- 
plasm that one can assume gives rise to drug reaction. If, however, 
the particular drug is of such nature as to enter into solution in the 
inactive tissue, then to that extent it is lost from the possibility of 
reaction with the active tissue. In old age there is less active tissue 
weight for weight than in the younger adult, hence pharmacological 
dosage must be somewhat reduced. 

V. 

Nature of the Change Induced by Drugs in the Pharmacological 
Actions of the Body. 

The human body is a highly differentiated mass of tissues and 
cells. The differentiation has resulted in two general types of struc- 
ture, first, the generalized tissues such as the skin, connective tissue, 
bone, etc. ; and second, the specialized tissues, i.e., the nervous tissue, 
muscular tissue, gland, etc. 

The first class of tissues is characterized by the possession of 
protoplasmic properties which retain, to a relatively high degree, the 
general characteristics of living protoplasm. These are the mobile 
tissues, the tissues on which growth, repair, and metamorphosis de- 
pend. These are the tissues which enter largely into the pathological 
processes, i.e., inflammation, tumor formation, and metastases. 

The specialized tissues are those that have modified widely from 
the general type for the effective accomplishment of some one or more 
of the special functions such as irritability and conductivity in the 
nervous tissue, contractility in the muscular tissue, and secretion in 
glandular tissue. These are the tissues which are least easily modified 
in their form but which are most strikingly involved in the execution 



12 PHARMACOLOGICAL FACTORS 

of specific functions. They are the tissues which, when subjected to 
the influence of drugs, respond most acutely with changes manifested 
in the group by dynamic phenomena. 

Of these two classes of tissue the first is involved in all those 
phenomena which are characterized by irritative processes. They 
are the tissues affected by such agencies as turpentine, arnica, dilute 
alkalies, iodine, cantharadine, etc. Those drugs which act upon the 
parenchyma, that is the specialized tissues, can produce, and do 
produce changes in the specific functions. 

These changes are of necessity of two types, an increase in the 
function, i.e., stimulation, or a diminution of the normal function, i.e., 
depressive. Also, this possibility applies to each differentiated part 
of the body. Therefore the possibilities of change in the total func- 
tions of an organism are great in proportion to the number of highly 
differentiated tissues and dependent relations of tissues found in the 
body. As an illustration, when caffeine is introduced into the general 
circulation, it increases the functional activity of the nervous tissue 
by increasing the irritability of that tissue. Under the influence of 
this alkaloid a smaller stimulus will produce the same nervous reaction 
as that produced by a much larger stimulus in the normal body. The 
cerebral cortex is therefore more susceptible to stimuli, hence gives 
a greater amount of response to the same stimulus. The general 
activities of the body, as a whole, are proportionally increased or 
restrained, therefore, because this controlling tissue of the cerebral 
cortex is increased in its function. Or, if atropine is used in sufficient 
quantity to depress the activity of the vagus nerve endings, the 
usual stimulations, which increase the function of the vagus, will fail 
of their ordinary effects upon the heart. The delicacy of coordina- 
tion, which is usually accomplished by the cardiac nervous apparatus, 
is lost owing to the blocking of conduction through the nerve endings. 
In a similar manner, when the ganglionic synapses of the autonomic 
system are under the toxic influence of nicotine, there will be a general 
depression of the delicacy of coordinative responses in the circulatory, 
respiratory, and glandular systems. Certain drugs, like the glucoside 
digitalis, increase the function of a large number of parenchymatous 
tissues at one and the same time. The intensive action of the drug is 
greater by virtue of this simultaneous action on numerous tissues. 
In a like manner the depressive action of morphine is greater because 
it lowers the reactive power of practically all of the tissues of the 
bodv. 



METHOD OF APPLICATION OF DRUGS 13 



VI. 

The Method of Application of Drugs as Modifying the Changes 
in Pharmacological Activity. 

The method of bringing the drug into contact with the body 
decidedly influences the character and the rapidity of reaction in- 
duced. It is possible to control the relative concentration and the 
sequence with which the drug is brought into contact with the differ- 
ent tissues of the body. One may exercise a certain amount of control 
over the rate and the degree of absorption, therefore the relative 
concentration of the drug in the different tissues at a given moment. 
The methods of presenting drugs to the tissues of man and mam- 
mals are briefly reviewed in the following paragraphs. 

i. Introduction of drugs by way of the mouth. — This method 
involves the slow process of absorption through the walls of the 
alimentary canal and is, therefore, a relatively slow method of in- 
troducing drugs into the general system. As drugs, like the elements 
of food, are absorbed chiefly in the intestinal tract, it follows that 
the rapidity with which they are passed into the intestine will de- 
pend upon the general motility and sensibility of the alimentary 
tract, particularly of the stomach. 

Drugs given by way of the mouth produce local effects in the 
mouth itself and in the stomach long before they reach the general 
system. All medicinal agencies with strong tastes and with positive 
odors sharply stimulate the sense organs of the mouth and nasal 
cavity. Reflexes are thus produced that induce secondary changes 
in the secretory, respiratory, and circulatory systems. Drugs taken 
by way of the mouth always reach the stomach and intestine in 
greater concentration than they will have after absorption. Thus 
strong alcoholic liquors, such as whiskies and gins, taken undiluted, 
produce marked local inflammatory processes in the stomach. After 
the slow process of absorption these alcohols are so far diluted that 
no general irritant effects occur, hence the characteristic general 
systemic effects alone are produced. 

2. The introduction of drugs by way of the rectum. — The rectal 
method of introducing drugs rests upon the well-known fact that 
absorption takes place from this region. Even volatile substances, 
as ether, have been given by this channel. It has the advantage of 
avoiding the mouth and stomach, if for any reason such path is un- 



14 PHARMACOLOGICAL FACTORS 

desirable. The local reflexes produced in the mouth and stomach 
are avoided and the cardiac and vasomotor reflexes are not so strongly 
aroused. It is well known that artificial feeding may be accom- 
plished by way of the rectum in instances of marked inanition or for 
other special reason. 

3. Hypodermic injection. — A small syringe provided with a fine 
hollow needle tip provides a convenient and reliable method of giving 
drugs. Sterile solutions are injected into the subcutaneous tissues 
whence they are rapidly absorbed into the general circulation. This 
method has certain objections, i.e., considerable pain is produced by 
the mechanical effects of the injection and the pain induces com- 
plicating reflexes. Certain drugs are marked irritants and set up 
local inflammation at the point of injection, as for example digitalin. 
Finally, there is always the risk of infection by the introduction of 
contaminating germs. 

Hypodermic injections may be used to secure the local action of 
drugs as well as to secure their general action after absorption. The 
best well-known illustration is that of cocaine. This general poison 
has proved of inestimable value in alleviating pain in operative and 
other procedures due to the successful hypodermic infiltration of the 
drug, care always being taken to prevent too rapid absorption so that 
a toxic quantity at any one time does not get into the general cir- 
culation. The hypodermic syringe is an invaluable instrument, not 
only in the determination of the facts of the pharmacological action 
of drugs, but in the control of drugs in practical therapeutics. 

4. Intramuscular injection. — Meltzer has proved that a more 
rapid absorption of drugs occurs if the injection be made deep into 
the body of the skeletal muscles rather than into the subdermal con- 
nective tissues. This method, therefore, is to be employed in all 
cases where it is desired to introduce the drug in the most rapid way 
other than intravenous. This method is proving very valuable. By 
it drugs are rapidly, and, what is often of more importance, evenly 
introduced into the general circulation. Furthermore there is less 
pain and a slighter tendency to local inflammation from preparations 
that tend to irritation. 

5. Intravenous injections. — The quickest and surest way of 
bringing a drug into contact with all the tissues is by introducing it 
directly into a vein. It thus passes throughout the whole circulatory 
system in a few seconds. Solutions are driven from a hypodermic 
needle or through a canula ligated into a vein. In either case pre- 
caution must be taken ; first, not to introduce air and thereby produce 



METHOD OF APPLICATION OF DRUGS 15 

air emboli ; second, not to introduce vigorous acting drugs too rapidly, 
lest they reach the heart in too concentrated form and lead to un- 
desirable reactions before general distribution is accomplished ; third, 
when either of these methods is practiced on man, or on any animal 
when the life is to be conserved, the whole procedure should be under 
aseptic conditions. 

6. Transfusions. — The transfusion of blood from one person to 
another is a most valuable clinical method of saving life. It is 
practiced in cases of extreme anemia, or where there has been great 
loss of blood under conditions from which the individual does not 
rally. In this method an artery, generally the radial of the donor 
is directly connected with one from the recipient, and blood is 
allowed to run directly from the vessels of the one to the other. In 
transfusion we now know that only the blood of individuals of the 
same species can be safely transfused (see literature on Animal Sera, 
Toxins, etc.). 

The method of transfusion is a reliable method of pharmacological 
testing as applied to animals. Valuable information as to the re- 
actions of epinephrine, or sera, etc., has been secured by this method. 

7. Inhalation and insufflation. — Everyone is familiar with the 
method of introducing volatile drugs by inhalation and insufflation 
as practiced in anesthesia. The volatile anesthetics, ether and chloro- 
form, as well as the gases, as nitrous oxide, carbon dioxide, or the 
poisonous carbon monoxide, are readily absorbed through the lining 
epithelium of the lungs. They are taken up by the blood in the pul- 
monary vessels and quickly distributed to all parts of the body. 

It is also possible to introduce substances which can be atomized 
and inhaled with the respiratory air. Such atomized particles come 
in contact with the pulmonary epithelium and are fairly readily 
absorbed. ' Volatile oils which are carried off on steam belong to this 
class of materials. 

8. Local application of drugs. — A favorite method for bringing 
drugs into contact with particular parts of the body is that of 
local application. This method is chiefly limited to external sur- 
faces of the body or those portions of the body that are readily 
reached through the external openings. Deeper portions of the 
digestive tract, such as the stomach and the rectum, admit of a 
limited application of drugs by this method. Also in hypodermic 
injections, as for example cocaine, drugs can be so manipulated as 
to produce strictly local effects. 

One of the best illustrations of the local application of drugs is 



16 PHARMACOLOGICAL FACTORS 

that of atropine to the surface of the eye. The alkaloid is slowly 
absorbed into the tissues of the cornea and the underlying parts, ' 
where it ultimately comes into contact with the musculature of the 
iris and ciliary processes. In this locality the atropine penetrates to 
the nerve endings of the smooth muscles involved in the act of ac- 
commodation where it produces its selective toxic action. It is true 
the atropine is absorbed into the general circulation, but only very 
slowly, and it does not reach the general tissues in concentration great 
enough to produce noticeable changes in organs other than the eye. 
If an excess of atropine be applied to the eye and its application too 
long continued, then there may be enough absorbed into the general 
circulation to become active. 

The method of local application is capable of wide use, especially 
in the group of irritants. Drugs that would be very toxic if introduced 
into the general circulation may be used by this method. Contact 
restricted to a local area, may still be associated with extensive and 
general physiological effects on the organism as a whole. These effects 
are, for the greater part, reflex in character, hence fall on the factor 
of coordination influences within the body. One of the chief values of 
the method of local application depends upon this reflex influence, an 
example of which is found in the reactions of the group of counter- 
irritants. 

VII. 

Changes Produced in the Reactive Power of the Individual by the 

Continued Application of the Drug — Summation and 

Tolerance. 

If drug doses are given in succession, two changes may follow 
in the intensity of the physiological reaction produced. First, if 
the doses follow in too rapid succession so that elimination is incom- 
plete there will be summation, or cumulative effects. This is illustrated 
by the usual therapeutic administration of digitalis. Mostrom 
and McGuigan x have explained certain increased sensitiveness of 
animals to strychnine as ' ' habit, ' ' or as Sollmann - puts it ' ' The 
system appears also to be subject to what might be called an ' educa- 
tion ' to the effects of the drug." 

However, the more striking and more common phenomenon is the 

1 Mostrom and McGuigan: Jour. Pharmacology and Exp. Therapeutics, Vol. 
III., p. 515. 

"Sollmann: Textbook of Pharmacology, 2d edition, p. 131, 1906. 



PHARMACOLOGIC VS. THERAPEUTIC ACTION 17 

great decrease in susceptibility as the dose is repeated, known as 
acquired tolerance. Acquired tolerance differs from individual tol- 
erance in that it implies an individual readjustment to the new agency. 
It is most strikingly illustrated in the instance of the numerous drugs 
that are abused leading to the formation of drug habits. The origi- 
nally sensitive tissues acquire an immunity whereby the organism 
may withstand the toxic action of a dosage many times greater than 
the ordinary fatal quantity. This is illustrated by the widespread 
nicotine habit, so prevalent in America, or the opium habit of the 
Orient, or by the worldwide prevalence of the alcohol habit. 

A few cubic centimeters of whiskey will produce incipient intoxi- 
cation in an individual not accustomed to its use, whereas a con- 
firmed toper may consume more than a pint or even a quart a day 
and still maintain his equilibrium. 

The organism acquires tolerance in several ways. There is an 
actual decrease in the protoplasmic sensitiveness to the drug as in the 
case of nicotine. Or the presence of the drug may lead to the 
strengthening of the defenses of the organism expressed in the in- 
creased oxidative power as with alcohol, or, in the production of 
neutralizing substances as in the case of the toxins. 

VIII. 

Pharmacologic versus Therapeutic Action. 

Pharmacological action is defined above as change induced in the 
normal physiological functions, whereas therapeutic activity is change 
induced in the pathological functions with the object of aiding the 
recovery of the normal. Eational therapeutics assumes that these two 
types of change are in the same direction, are alike in kind. How- 
ever, pathological states induce great changes in an organism along 
two lines. There are changes in the protoplasm itself, and these are 
more or less responsible for changes in the interrelations of parts, 
hence in the functional coordinations. The diseased condition is the 
sum of these two classes of changes. Pathological protoplasm will 
not always give the same quantitative responses to a drug as does the 
normal, in fact there are certain qualitative variations as well. In 
general the response is of a similar quality, but varies more widely 
quantitatively. The greatest difference lies in the change in the type 
of responses in the great coordinative mechanisms. It is evident that 
familiarity with pharmacological action is a necessary foundation 



18 PHARMACOLOGICAL FACTORS 

for therapeutic applications. But the latter must take into considera T 
tion the changes induced by the pathological states produced by dis- 
ease, hence the corresponding variations in the response to drugs. 
This field is now rapidly being brought to a more accurate scientific 
basis by the development of the newer field of experimental 
therapeutics. 

IX. 
The Fate of Drugs in the Body. 

Drugs are disposed of by the body in several ways. Certain 
drugs, as alcohol or morphine, are largely oxidized by the tissues. 
From 90 to 95 per cent, of the alcohol of liquors is oxidized, leaving 
only a small percentage to be disposed of in other ways. 

Excretion by the kidney, the skin, the lungs, in volatile substances, 
or by the alimentary tract is the usual fate of most substances. The 
material may be excreted unchanged or it may be partially oxidized 
and then excreted. Substances that are excreted by the alimentary 
tract are partially resorbed by lower divisions of the tube, hence 
their elimination by this route is through an ever-repeating circle and 
slow. Morphine is an example. It is excreted freely into the stomach 
and reabsorbed from the intestinal tract further on. The heavy 
metals, which form very fixed chemical combinations in the body, 
are dissociated and eliminated only with extreme difficulty and in 
minute quantities at a time through the kidneys or the alimentary 
tract. Most volatile substances are rapidly eliminated through the 
pulmonary epithelium and carried off in the expired air. Ether and 
chloroform are typical of this class. 

The chief excretory channel for the great majority of drugs is 
the kidney, the substance being eliminated hr solution in the urine. 



PART I. 
ORGANIC DRUGS. 

A. General Depressant Series. 



CHAPTER II. 
THE ALCOHOL GROUP. 

I. 

Introductory and Chemical. 

Introduction. — Of the alcohol chemical series the form most in- 
teresting from the pharmacological standpoint is ethyl-alcohol, 
C 2 H 5 OH. This alcohol is the particular constituent of a long series 
of fermentive beverages and has been known since the beginnings 
of history. The use of alcohol and alcoholic beverages in medicine 
also dates to the earliest known period. It does not seem necessary 
in this connection to trace the historical steps down to the present 
time in relation to either the medical or social use of alcoholic prep- 
arations. Perhaps it is sufficient to say that in the last few years 
the reactions of alcohol in the body have been studied both quali- 
tatively and quantitatively in the light of our modern advances of 
physiology and physiological chemistry. The result has been to give 
this substance a much more rational position in the list of phar- 
macopeial remedies than it has ever known before. 

Solutions and chemical relationships. — Ethyl-alcohol is derived 
from the fermentation of different sugars by yeast. The reaction 
that takes place in general can be represented by the formula : — 

Glucose Alcohol Carbon dioxide 

CH O = 2 C H OH + 2 CO 

6 12 C 2 5' 2 

Absolute alcohol is a transparent, highly volatile substance with a 
specific gravity of 0.797. It boils at a temperature of 78.5° C. The 
ordinary commercial alcohol contains about 95 per cent, absolute 
alcohol. 

The alcohols used in medicine are rarely pure alcohols. Instead 

19 



20 THE ALCOHOL GROUP 

are used the alcoholic liquors, such as whiskey, wines, brandies, etc. 
Liquors contain a varying percentage of alcohol depending upon the 
particular class to which they belong. 

Brandies, whiskeys, and rum 40-60% alcohol. 

Wines 6-22% 

Beer 3-6 % 

Ales 2-5 % 

Liquors always contain a number of principles more or less volatile 
which bear a close chemical relation to or are developed during the 
fermentation of the alcohol. It is these substances that give the 
characteristic aromas and flavors peculiar to the different types of 
liquors. The development of the flavoring materials depends largely 
upon the type of yeasts fermenting the fruits and grains, but to 
some extent upon the character of the fruits and grains used. It is 
this characteristic of the local brews of liquors from special localities 
which is prized so highly by connoisseurs, as for example in the 
different Rhine or Spanish wines. 

The alcohol series varies in toxicity or in intensity of pharma- 
cological action somewhat in relation to the structural formula of 
the particular alcohol. In general it can be said that the intensity 
of the toxic action increases as we go up the aliphatic series. The 
toxicity -of the first five members is as follows, according to Baer: 

Methyl CH g OH Toxicity . 8 

Ethyl C H OH " 1,0 

Propyl C 3 H ? OH " 2.0 

Butyl CH g OH " 3.0 

Amyl C.H^OH " 4.0 

In the higher members of the series the solubility of the substances 
in the body fluids becomes relatively less and therefore the toxicity 
falls off, the paraffins being wholly insoluble and inert. 

II. 

Alcohol as a Local Irritant. 

i. The local effects of alcohol on the skin. — When alcohol is 
applied to the skin at any point on the surface of the body in 
relatively concentrated form it produces a local irritative process 
in the epidermal tissues. Under ordinary conditions the alcohol 
evaporates before the irritation proceeds very far and the effect is 



ALCOHOL AS A LOCAL IRRITANT 21 

slight and evanescent. But if the alcohol is kept from evaporating, 
then the irritation may proceed even to advanced stages of inflam- 
mation. The alcohol itself penetrates the skin rather freely due to 
its solubility in the oils of the surface. As it comes into contact 
with the deeper layers of the epidermis it extracts water and tends 
to precipitate the cell proteins, changes that account for the in- 
flammatory process. 

The local action is twofold. In the first place, it produces a 
primary stimulative effect on the processes of repair and growth. 
If the primary action of the alcohol is intense enough there may follow 
in definite pathological sequence the changes which characterize the 
development of inflammation. In the second place, an immediate 
stimulation is produced on the nerve endings in the local portion 
of the skin. The result of the stimulation is a series of reflexes 
which may affect not only the local circulation of the part, but also 
the general circulation, and, in the more extreme cases, the processes 
of respiration and the general bodily movements. The secondary 
effects are of course not peculiar to or characteristic of alcohol only, 
since they are characteristic of any local stimulative agent. 

2. The local effects of alcohol on the mucous membrane of 
the mouth and stomach. — Alcohol and alcoholic liquors produce 
distinct physiological responses when taken by way of the mouth. 
These responses are more marked with the liquors than with the 
pure alcohol, due to the fact that they contain esters and other 
volatile constituents which produce striking reflex stimulations. 

The local effect of the strong alcohol as such on the moist 
mucosa of the mouth and of the stomach is much more irritative 
than in the case of the skin. These membranes have a higher water 
content and the living protoplasm is not separated from the alcohol 
by a thick layer of dead tissue as in the skin. Therefore, the changes 
produced are immediate and stimulative leading to marked nervous 
reflexes through the medullary centers. It is at this point that 
one can make the strongest claim for the clinically beneficial effects 
of certain classes of alcoholic liquors. The mild stimulation of the 
taste buds in the mouth, and of the olfactory membrane of the 
nose, produces secretory reflexes through the medulla which not 
only increase the secretion of saliva but also induce the primary 
secretion of the gastric juice in the stomach, and possibly also the 
secretion of the pancreas. The painful and burning sensation of the 
stronger alcohols in the mouth may set up to some extent the same 
reflexes, but they are not so normal or beneficial. 



22 THE ALCOHOL GROUP 

In the stomach the mild irritation of the mucosa produces some 
degree of reflex secretion of gastric juice, a matter that has been 
adequately determined by Chittenden. Undoubtedly the stronger 
alcohols, especially when oft repeated, produce more profound 
processes leading to inflammation and ofttimes to necrosis. The 
necrotic ulcers of the chronic alcoholic are sufficiently well known. 
Certainly in such cases the gastric mucous membrane has long since 
passed into a pathological state in which even a normal secretion 
cannot take place, much less the favorable physiological reflexes. 

This local action of alcohol rests on its toxicity to general proto- 
plasm. It is this factor which makes of alcohol a valuable antiseptic. 
Isolated organisms, such as bacteria, protozoa, etc., have their proto- 
plasm precipitated by alcohol of sufficient strength and are therefore 
killed. 



III. 
Detailed Systemic Effects of Alcohol. 

i. The action of alcohol on the central nervous system. — 
Alcoholic liquors have long enjoyed a popular reputation as stimu- 
lants for the nervous system. Experimental tests have been made 
which claim for alcohol in very moderate quantities some acceleration 
of mental reactions, when tested by psychological tests and methods. 
Yet, writers working under such stimulus have not consistently 
found an increased brilliance of their products judged under calmer 
conditions. The question can safely be considered as still in doubt 
as to whether alcohol in such quantities favors or hinders the process 
and reactions of the central nervous system, the phenomena of 
which are expressed in mental or psychical states. 

It is generally admitted that larger doses of alcohol depress 
intellectual functions, and along with this depression will come 
marked changes in the general physiological reactions of the body. 
We are, in America at least, all too familiar with the details of the 
successive stages of the toxic effect of alcohol. However, some of 
the salient phenomena will be re-enumerated for the sake of clearness 
of discussion. 

In the first stage or in mild alcoholic action the individual 
changes in his personal estimate of his activities. The drinker fools 
that he is more brilliant, whether or not he be so. There is a 
greater vivacity, especially in company, usually associated with de- 



ALCOHOL ON THE NERVOUS SYSTEM 23 

creased reserve and self-restraint. The individual has what super- 
ficially appears to be a keener appreciation of humor and wit, that 
is, he gives greater responses to these stimuli. He shows a tendency 
to much talking, to free laughter, and also to accelerated neuro- 
muscular activities. The respiratory rate is generally somewhat 
accelerated, as is also the heart rate. An increased flushing of the 
skin, especially noticeable in certain portions of the face, is one of 
the first indications of mild alcoholic effects, an index which comes 
even earlier than those symptoms noted above. 

In the second or successive stage of alcoholization there comes on 
a more marked degree of incoordination of mental processes indi- 
cated by less logical sequence of thought. This characteristic is 
shown in the responses to wit, humor, etc., i.e., in responses to social 
intercourse. Along with these symptoms there is an increasing lack 
of neuro-muscular control revealed by some unsteadiness of move- 
ment as indicated in the process of writing, in the movements of 
walking and the like. 

With the still greater increase in the effects of alcohol there is 
a marked depression of the entire bodily functions. This is char- 
acterized bj r a progressive loss of muscular control to the point of 
narcosis, associated with increasing loss of normal reflex nerve re- 
actions, a depressed respiratory rate, a slower heart, and inefficient 
circulation. In this stage, especially when much prolonged, there 
is a decided lowering of the general body temperature. 

2. Explanation of the nervous symptoms induced by alcohol. — 
Two schools have arisen for the explanation of the influence of alcohol 
expressed through the nervous system. These two schools are led by 
the two great pharmacologists, Binz and Schmiedeberg. Binz and 
his followers believe that the incipient effects of alcohol on the central 
nervous system, including the cerebral cortex, are actual stimulation, 
that the functions are really accelerated. They of course admit that 
the later effects are narcotic. Schmiedeberg and his followers, on the 
other hand, believe that the incipient effects of alcohol on the central 
nervous system are narcotic and not stimulative. They explain the 
phenomenon of apparent accelerated function by the view that the 
narcotic effect of alcohol is progressively toxic, beginning with the 
highest portions of the cerebral cortex and extending in a descending 
direction, a process that characterizes certain dementias and is 
known as dissolution. The higher processes of the association centers 
of Flechsig through which the processes of reasoning, of attention, 
and mental association are executed will be first attacked by alcohol 



24 THE ALCOHOL GROUP 

and, by Schmiedeberg 's view, should be lowered in efficiency. 
Numerous later observers have found evidence to indicate that this as- 
sumption holds. Simple mathematical processes take place less readily 
when the computer is given a small quantity of alcohol. Also com- 
putations of distance as well as acuteness of perception are depressed. 
Typesetters do less work, i.e., place fewer type and with less accuracy, 
on days when they receive a small measure of alcohol. 

The accelerations of simple motor processes, which in their most 
complex form are associated with psychic reflexes, are explained 
on this view by the elimination of the inhibitive regulative control 
which the psycho-motor centers receive from the higher centers of 
the cortex. In progressive alcoholism there will come, therefore, a 
time when the association centers will have been narcotized just 
sufficiently to depress their inhibitive regulative control over the basic 
motor centers. These centers, therefore, will be physiologically freer 
to respond to the incoming sensory stimulations of whatever kind. 
The resultant reflex motor responses will be greater. The alcoholic 
therefore talks more volubly, laughs more freely, and responds more 
strongly to the stimulations of his social environment. These in- 
creased responses are by this line of reasoning to be considered as 
evidences of lack of control rather than positive stimulation. 

If one follows the progressive influence of alcohol in its inter- 
mediate and advanced stages he will note that the marked depres- 
sion of function appears successively in certain nerve centers, and 
this order is surprisingly near the ranking one would make on 
physiological evidence when asked to classify these centers in a 
descending series. There is first a loss of psychological activities, 
perhaps even of consciousness itself. This is followed by lack of 
motor control, especially of the arms, legs, and vocal apparatus in 
which the complexity of nerve structure and function is unques- 
tionably of later physiological development. Finally there is loss 
of function of the trunk musculature, therefore of the respiration, 
and a marked depression of the circulation, together with paralysis 
of those medullary centers controlling the same. 

3. The action of alcohol on the nervous system of lower 
animals. — The general influence of alcohol on intelligence as expressed 
by the action of the cerebral cortex has been tested on dogs by 
Hodge of Clark University. He found decided changes in the mental 
characteristics of dogs, particularly indicated by a great increase 
of timidity and fear, the especial symptom of the neurosis in man. 
The evidence of intellectual power he tested in four dogs of the same 



ALCOHOL OX THE NERVOUS SYSTEM 25 

species, by the method of retrieving. Two alcoholics, that is dogs 
receiving a definite quantity of alcohol in their food each day. and 
two normals were used. These dogs retrieved a ball on the gymnasium 
floor. The alcoholic dogs were far less efficient than the normal. 
Of a series of 1400 balls thrown "The two normal dogs retrieved 
922. the alcoholics 478. This gives the alcoholics an efficiency of 
59.8 per cent, as compared with the normals." Of the two male dogs 
the ability of the alcoholic was only 32 per cent, of the normal. The 
pair of alcoholics " gave evidence of very much greater fatigue." 
Of course the greater efficiency of the normal dogs in these tests 
rests in part in physical agility and muscular endurance as well as 
on nervous characteristics. 

4. The duration of the effects on the central nervous system. — 
The duration of the effects of alcohol varies with the size of the dose. 
If the amount of alcohol has been sufficient to produce the second 
set of changes previously outlined, then the body will not recover 
its former degree of activity for some fifteen to twenty-four hours 
or even more. The duration of the change is longer than has generally 
been supposed. Experiments have been carried forward to prove 
these effects on quantitative work as well as on qualitative. Dyna- 
mometer experiments by which one measures the amount of muscular 
work given off in voluntary muscular contractions tend to show that 
the effects of alcohol are recovered from very slowly. Voluntary 
muscular effort has in it two factors, the nerve stimulation and the 
muscular response. The action of alcohol is not the same on the 
two tissues. Hence the results of this type of test have been a little 
confusing. Jacobi's observation, that an individual could more clearly 
estimate small differences in weight when under small doses of alcohol 
than in the normal state, can be explained on the ground that the 
muscle itself is rendered less stable by the drug. It was shown by 
Lee and Salant that muscles execute the simple muscular contractions 
more quickly when subjected to moderate quantities of alcohol. In 
Jacobi's experiment it is not necessary to assume an increased sensi- 
bility of the nervous part of the apparatus, i.e., of the motor centers. 

An interesting observation was made by C. C. Stewart * showing 
that alcohol brought about a change in the amount of Xissl substance 
in the cells of the different portions of the brain, tending to diminish 
the content of the Xissl substance. Illustrations of the change in 
the pyramidal cells is shown by Figure 1. In light of later work- 
on the structural changes in nerve tissue under the influences of 
1 Stewart, C. C. ? Journal of Exp. Med., Vol. I., p. 623, 189(». 



26 



THE ALCOHOL GROUP 



activity, drugs, etc., it is probable that this stage of change rep- 
resents only a mild degree of acute activity quite comparable to that 
shown by vigorous activity of ordinary type. Whether or not alcohol 
produces the more profound changes observed under other conditions 
remains yet to be learned. 

5. The action of alcohol on muscular tissue. — The muscular 
apparatus consists of the muscle fibers, the controlling motor nerves, 
and the nerve endplates which unite the two. The evidence showing 
the action of alcohol on the nervous tissue applies to the motor 
cells of the spinal cord and brain stem, though these cells are 






Fig. 1. — Alcohol on the amount of Nissl suhstance in pyramidal cells ; 1, normal ; 
2, alcohol for 50 minutes ; 3 and 4, alcohol for 54.5 hours. Stewart. 

somewhat less sensitive than other portions of the nervous system. 
Nerve fiber itself can be narcotized by alcohol as has been shown 
by Waller, in this instance preceded by evidence of stimulation. 
Muscle has been studied extensively by Lee and Salant, 1 who showed 
that there is a distinct increase both in the sensitiveness of the 
muscle to stimulation and in the amount of work which a muscle 
will do under repeated stimulation. Also, the number of contrac- 
tions which can be completed in a given time is greater, since the 
individual contractions are quicker. These three effects are observed 
only on muscle which has received a relatively moderate quantity of 
alcohol, preferably through the blood vessels. When the dosage is 
greater, then the reverse of the above effects is true. Lee and Salant 
compared the two gastrocnemii of the frog, one of which received 
alcohol, the other none. When after a mild injection of alcohol both 
are stimulated uniformly with single induction shocks repeated, say, 
every two seconds, which allows time for a complete relaxation of 
the muscle after each stimulus, and if the stimulation be kept up 
until the muscles are exhausted the alcoholic muscle will give off a 



Lee, F. S., and Salant, W„ Am. Jour. Physiol, Vol. VIII., p. 61, 1902. 



ALCOHOL ON THE HEART 27 

greater amount of work than the non-alcoholic. Comparison of the 
two records shows that the alcoholic muscle lifts the same weight 
through a greater height and that the number of contractions is 
greater. On the other hand, if a strong dose of alcohol be used just 
the reverse results are obtained. The alcoholized muscle does the 
least work. These results, which have often been repeated and con- 
firmed in our pharmacological laboratory, seem to prove that the 
muscle substance as such is a little less stable under the influence 
of a mild amount of alcohol. The decrease in stability permits a 
quicker response upon stimulation, a result that can be explained 
on the assumption of increased irritability. 




Fig. 2. — Curves of simple muscle contraction from the gastrocnemii of the frog. 
The quick contraction, after 0.08 cc. of 10 per cent, alcohol to 1 grm. of body weight. 
The slower contraction, the normal muscle before alcohol. Lee and Salant. 

It would seem, therefore, that skeletal muscle as such may receive 
a true stimulation by alcohol. This is of little practical value, 
however, since all voluntary muscular activity calls for the nervous 
stimulating factor. Nerve cells have already been shown to be nar- 
cotized by alcohol. These two antagonistic effects upon the neuro- 
muscular apparatus have served to suppress the real truth for each, 
and have led to confusing interpretations in many lines of experi- 
ments such as voluntary muscular work. 

No evidence has yet been adduced showing any favorable influence 
of alcohol on smooth muscle, and in cardiac muscle alcohol is on the 
whole depressant. 

6. Alcohol on the heart and circulatory system. — " Alcohol, 
when circulating in the blood stream, causes a gradual progressive 
lowering of blood pressure, with decrease in amplitude, but increase in 
the rate of the heart beat," according to Brooks whose experiments 
were uncomplicated by the presence of anesthetics. This systemic 
effect is due to a series of factors involved in the circulation, namely, 
those which on the one hand control the action of the heart, and on the 
other control the size of the blood vessels, and therefore the peripheral 
resistance to the flow of blood. The reaction on the circulatory 



28 THE ALCOHOL GROUP 

system is abundantly complicated, however, by physiological factors 
set in action by the local stimulation by alcohol and the alcoholic 
liquors when taken by the mouth. 

v a. The reactions of the heart. — The heart is a complicated 
apparatus, physiologically consisting of the musculature of the heart, 
the local nervous apparatus, and the nerve centers and connections 
with the central nervous system. There are well defined methods 
in vogue in physiological and pharmacological laboratories for study - 




Fig. 3. — Alcohol on ventricular muscle. The strip contracts rhythmically in physi- 
dlogical saline 9 parts plus Ringer's solution 1 part. During the time indicated by 
the marker 2 per cent, alcohol in the normal solution was applied. The time record, 
intervals of 10 seconds. The second test was depressing. New tracing by Summers. 

ing each of these portions of the cardiac apparatus. To determine 
the effects of alcohol on cardiac muscle two methods have been 
used. One method depends upon the isolation of the muscle itself, 
heart strips as free as possible from nervous elements, and the 
immersion of these strips in solutions of alcohol made up in normal 
or artificial physiological liquids. The other method consists in per- 
fusing alcoholic solutions through the isolated heart or through the 
heart in place in the body cavity. Studies on the strips of cardiac 
muscle, for which the heart of the terrapin is especially favorable, 
show that alcohol depresses both the rate and amplitude of the mus- 
cular contractions. Stimulative effects, as indicated by accelerated 
rhythm, very seldom occur, in not over 10 per cent, of the experiments. 
These accelerations are produced by relatively strong solutions of 
alcohol and only at the moment of immersion. This suggests the type 
of local irritative effect rather than a pharmacological stimulation. 



ALCOHOL OX THE HEART 29 

Increase in amplitude, which is so characteristic of the isolated 
skeletal muscle, does not often occur on isolated strips of heart muscle. 
The exceptional reaction is presented in Figure 3. 

Perfusion of alcohol through the heart of the frog has, in the 
main, given confirmation of the observations from the muscle strips 
taken from the terrapin. The amplitude of the frog's ventricle 
diminishes and the rate becomes slower and often ceases, even with 
the weaker solutions. It is admitted by all that the stronger con- 
centrations, 1 per cent, and over, are depressant. The auricles are 
even more sensitive than the ventricle. They dilate and become 
extremely feeble. Conduction of the auriculo-ventricular wave 
diminishes or is blocked. 

Experiments on the isolated mammalian heart have, in the main, 
given essentially the same results as those listed above for the cold- 
blooded animals. Martin and Stevens 1 were the first to investigate 
the behavior of the isolated mammalian heart under the influences 
of alcohol added to the blood perfusing through it. Their results 
are indicated in the following quotation : 

" When defibrinated blood containing one-half of one per cent, 
by volume of ethyl-alcohol is supplied to an isolated dog 's heart, 
which has been hitherto working with uniformity, the invariable result 
is a very rapid and marked diminution in the work done (indicated 
by the quantity of the blood pumped out from the left ventricle) by 
the heart in a given time. When the blood contains only one-fourth 
of one per cent, of alcohol the result is, in most cases, the same, but 
sometimes is little or none. After the action of the alcohol has been 
fully manifested the heart can, in many cases, be restored to its 
original working state if supplied with defibrinated blood containing 
no alcohol. Blood containing but one-eighth of one per cent, of alcohol 
exerts no influence upon the work done by the heart, at least for 
several minutes/ ' 

Leo Loeb's experiments on the perfused and isolated heart showed 
that when alcohol was added to the perfusing fluid to the amount 
of 1 per cent, and more the solution became injurious to the heart. 
There was diminution in the rhythm and weakening of the force 
of the contraction. "When he used solutions of 0.3 per cent, or less 
he sometimes found a stronger heart beat. This was particularly 
true if the heart was in a weakened condition. Dixon 2 further 

1 Martin, N. H., and Stevens, L. T., Jolins Hopkins Biol. Bull, Vol. II. , p. 
485, 1883. 

2 Dixon. W. E., Jour. Physiology, Vol. XXXV., p. 346. 



30 



THE ALCOHOL GROUP 



elaborated this point and secured a decided improvement in the cardiac 
flow and rhythm by concentrations of alcohol from 0.05 to 0.3 per 
cent. The favorable influence on the heart action was decidedly 
greater when the hearts were in a weakened condition. Cushny, in 
his Pharmacology and Therapeutics, publishes a splendid instructive 
figure (Fig. 3), which shows the unfavorable influence of alcohol as 
falling more strongly on the contractile power of the auricle. This 
effect would markedly influence the volume and therefore the efficiency 
of the cardiac discharge even though the ventricle were less pro- 
foundly affected by the drug. 

Isolated hearts contain local ganglia as well as muscle. But 
such stimulations as do occur can scarcely be claimed as specific or 
constant enough to be attributed to the nervous elements. Hence, 
whichever view one takes of the cause of the heart rhythm and 
sequence, the pharmacological explanation of the direct action of 



■■■■ LI?!'!! i ■ ■■■!* 




p IG . 4. — Isolated Rabbit's heart perfusing with Ringer-Locke solution. A, normal ; 
B, after two minutes with 0.4 per cent, alcohol ; C, alcohol 0.8 per cent. Time in 
seconds. Dixon. 



alcohol on the heart is the same, namely, primary depression of 
function. 

o. On the cardiac centers of the medulla. — It has been diffi- 
cult to determine the direct action of the weaker doses of alcohol 
on the cardiac medullary centers because of the complicating reflexes. 
Also in an experimental procedure on mammals the medullary center 
is almost always rendered somewhat narcotized by the anesthetics 
employed. Dixon, however, has published results of experiments in 
which he used the beheaded dog. He injected alcohol into the carotid 
artery but toward the medulla. His published figures show a prompt 
but temporary rise of blood pressure and a change in the heart beat. 
A previous injection of 5 cc. of 30 per cent, alcohol in the jugular 
vein led to a marked fall of blood pressure. Dixon's figure presented 



ALCOHOL OX BLOOD VESSELS 



31 



herewith gives his evidence for assuming that the inhibitory cardiac 
centers are directly stimulated by alcohol. 

Brooks gave alcohol by the mouth, through a gastric fistula, and 
intravenously. The rise of pressure which he found on giving alcohol 
by the mouth he ascribes to a reflex stimulation. Brooks, by a more 
normal method, excludes any direct stimulative action on the niedul- 




Fig. 5. — Dog, cerebrum destroyed, but medulla uninjured. The records from 
above downward are respiration, intestinal volume, and blood-pressure. At the mark 
X 10 cc. of 30 per cent, alcohol was injected into the femoral vein. The right and left 
vagi were cut at the marks indicated to the right. Time in seconds. Dixon. 



lary center. Here again, therefore, we have the matter still in dis- 
pute and one must draw his conclusions guardedly. 

c. On the peripheral blood vessels. — The arteries are under a 
partial tonic contraction controlled by the nerves emanating from 
the vasomotor centers. Under the influence of alcohol these muscles 
relax, thus leading to a dilatation of the blood vessels. Dixon has 
reinvestigated this question, showing that there is with light doses 
an associated vascular constriction in the viscera. This positive 
visceral reaction he believes to be largely central, involving an asso- 
ciated alcoholic stimulation of the heat regulative centers. The 
stronger and semitoxic concentrations tend toward a general vascular 
paralysis, not only in the skin but in the viscera as well. 

The cutaneous dilatation is shown in the blush that comes in the 



32 THE ALCOHOL GROUP 

cheeks and face of those who use alcoholic liquors even very sparingly. 
This blushing takes place more or less throughout the whole skin 
and gives rise to the feeling of warmth and glow which characterizes 
the early effects of alcohol. Undoubtedly the sensation is one second- 
arily produced by the slight rise in temperature of the skin associated 
with the dilated blood vessels. It is this factor which makes possible 
the great loss of heat even in the mild stages of alcoholism. It is 
an oft observed fact that those who take a " bracer " of alcoholic 
liquors in bitter cold weather cannot resist the extreme cold nearly 
so well as those who refrain. The dilated cutaneous blood vessels lead 
to a greater loss of heat than the body can supply, hence a lowering 
of the body temperature. 

Continued use of alcohol tends to a permanent paralysis of the 
cutaneous blood vessels. This paralysis is particularly striking in 
the cheeks and especially in the nose in chronic alcoholism. It is 
accompanied by degeneration of the active muscular tissue of the 
smaller arterioles, probably associated with decreased endothelial 
resistance and with fibroid thickening of the vascular walls, all of 
which contribute to a pathological condition of the tissues of the 
part. 

7. The action of alcohol on the blood. — ' ' Alcohol has a harmful 
action on the white blood cells, the agents of natural defense against 
infective microbes " (Metchnikoff). The corpuscles are rendered 
less motile and therefore are decreased in their phagocytic action. 
Certain microbes, especially those of erysipelas, are shown to more 
readily gain a foothold in the body when the phagocytes are ren- 
dered relatively inert by alcohol, and it is also shown that alcohol 
users are prone to suffer from this disease. 

As was to be expected, the blood complements have also been shown 
to be distinctly reduced in users of alcohol. The importance of this 
change in the blood can scarcely be over-estimated in its relation 
to the establishment of immunity. 

Neither do the red corpuscles escape injury by alcohol, due to 
the relative solubility of alcohol in the red corpuscle substance. As 
a result, large numbers of corpuscles are weakened and ultimately 
destroyed. The continued display of alcohol therefore has a tendeney 
to the production of anemia. 

A not unimportant secondary influence of the consumption of 
large quantities of the lighter alcoholic liquors is its influence on 
the volume of the blood. The continued absorption and disposal 
of large quantities of fluid tend to raise the total volume of the 



ALCOHOL ON THE DIGESTIVE TRACT 33 

blood and this reacts in the complex of the circulatory system to 
increase the work of the heart. The prolonged effect of this condition 
is great hypertrophy of that organ. Such liquors are generally asso- 
ciated in the long run with sufficient concentration of alcohol to 
produce muscular degeneration so that the beer drinker's heart 
becomes, not only excessively hypertrophied, but also weakened by 
fatty degeneration and infiltration. 

8. Responses of the respiratory system to alcohol. — Alcohol 
affects the respiratory mechanism at two points, namely, the ap- 
paratus which controls the volume of air expired, and, second, that 
which controls the carrying power of the blood as regards its oxygen, 
Binz has given evidence indicating that alcohol slightly stimulates 
the respiratory centers, especially in the case of wines. Measure- 
ments have been made indicating that the total respiratory volume 
is increased with small doses of alcohol. Attention must again be 
called to the effect of alcohol on the nervous system. If one accepts 
the view of the depressant action of alcohol of the Schmiedeberg 
school, then it is obvious that this increase of respiration would 
take place as a secondary effect of the alcohol, either from the progres- 
sive narcosis of cerebral centers, or from reflexes arising in the mouth 
and stomach. In any case the acceleration of respiration is evanescent, 
passing quickly into a stage of depressed rate and amplitude, and the 
total air breathed is less. Dixon's figure shows primary respiratory 
depressant action, Figure 5. 

The influence of alcohol on the blood whereby the total amount 
of hemoglobin is diminished produces a chronic diminution in the 
internal respiration. Such an effect would not follow after a single 
dose. 

9. The action of alcohol on the digestive tract. — The local irri- 
tating effects of alcohol on the alimentary tract and the secondary 
reflexes produced thereby have already been discussed. It should 
be remembered that the acute secondary effects of alcohol produced 
through stimulation of the nervous mechanism which controls the 
secretion of both the salivary and the gastric glands are favorable. 
When alcohol has been absorbed and, through the blood, reaches these 
glands and their nervous mechanisms, secretory action is apparently 
accelerated in the gastric glands but not influenced in the salivary 
glands, according to Chittenden. 

Alcohol mixed with the foods in the digesting stomach produces 
an increase in the absorbing powers of this organ. This is to be 
attributed to the direct effect of alcohol on the superficial epithelial 



34 THE ALCOHOL GROUP 

cells whereby these cells are rendered more permeable than normal. 

Extensive experiments have been performed to show the action of 
alcohol on the digestive enzymes as such. These experiments indicate 
that the total efficiency of the digestive enzymes is decreased only 
after an alcoholic concentration of from 5 to 10 per cent. If one 
adds the two factors, increase in the total secretion of enzyme and 
the decrease in the efficiency of the enzyme present, it is obvious that 
the total efficiency of the digestive enzymes as such may be accelerated 
or weakened pretty much in proportion to the concentration of the 
alcohol. In therapeutic quantity and with guarded administration 
the medicinal balance is favorable in certain maladies. 

Excessive quantities of alcohol tend to diminish the motility of the 
stomach and intestine, a change that is unfavorable to digestion. 
If the peristalses of the stomach fail to occur in the normal number 
and intensity then the food will be relatively stagnant in the stomach 
and fermentive and other changes are induced which are detrimental. 
This is an important factor in the development of secondary toxic 
substances. Where the local action of alcohol has resulted in exten- 
sive gastric ulcers both secretion and motility are interfered with, 
and digestion is rendered correspondingly less efficient. 

io. The liver in relation to alcohol oxidations. — The physiolog- 
ical importance of the liver is very great, a fact that is realized when 
one recalls the numerous functions accomplished by this organ. The 
discovery of the glycogenic function of the liver by Claude Bernard 
in the middle of the last century gave such importance to this func- 
tion as to overshadow the several no less important functions that 
have been explained in more recent times. Of all the complex func- 
tions of the liver one cannot overestimate the part it plays in the 
elimination of nitrogenous wastes. Urea and uric acid are oxidized 
to their final form through the agency of the liver. The other 
nitrogenous wastes are oxidized or their elimination facilitated through 
the agency of enzymes which are present in the liver. Chittenden 
warns in the following terms : " It is, I think, quite plain that while 
alcohol in moderate amounts can be burned in the body, thus serving 
as food in the sense that it may be a source of energy, it is quite 
misleading to attempt a classification or even comparison of alcohol 
with carbohydrates and fats, since, unlike the latter, alcohol has a 
most disturbing effect upon the metabolism or oxidation of the purin 
compounds of our daily food. Alcohol, therefore, presents a danger- 
ous side wholly wanting in carbohydrates and fats. The latter are 
simply burned up to carbonic acid and water, or are transformed 



ALCOHOL ON METABOLISM 35 

into glycogen and fat, but alcohol, though more easily oxidizable, is 
at all times liable to obstruct, in some measure at least, the oxidative 
processes of the liver. ' ' The evidence indicates that the oxidation of 
alcohol itself takes place largely through the agency of the liver. 
In the presence of alcohol a relatively large amount of uric acid and 
a decreased quantity of urea are produced by the body. 

Clinically it is a well-known fact that certain diseases of the 
liver are associated with chronic alcoholism. Of these one of the 
most common is cirrhosis. The drug not only acts on the peripheral 
hepatic blood vessels and parenchyma directly, but the view has been 
offered that the energy of the liver is consumed in the oxidation and 
elimination of alcohol. There is, therefore, an accumulation of 
nitrogenous wastes that weakens and poisons, not only the body, but 
the liver itself. The excessive accumulation of uric acid is offered 
as an explanation of the tendency to gout in alcoholics. 

ii. The effect of alcohol on metabolism. — The oxidation of 
alcohol by the body sets free its latent energy, which no doubt is 
utilized. However, the presence of the alcohol interferes with the 
metabolic processes of the body itself. In a general way it tends to 
depress these changes. Alcohol, when given with a fixed ration, 
produces a diminution in the output of nitrogen and of the total 
sulphur which are perhaps the best measures we have of the influence 
of the drug on metabolism. The variations in the specific functions 
of so many different mechanisms, as outlined above, all point in 
the same direction. The use of alcohol, therefore, as an energy 
producing material, is overbalanced by its toxic injuries. Even the 
energy which it gives is more than compensated by the weakening 
of the oxidizing organ, the liver. 

Hunt has more recently given us an insight into the nature of 
the change in metabolism initiated by alcohol. He has worked with 
minimal and non-toxic doses fed to different species of animals 
through relatively long periods. He has shown, for the first time, 
that such temperate use of alcohol leads to marked changes in the 
by-products of metabolism. Proceeding on the theory that tolerance 
presupposes increased ability of the tissues to oxidize alcohol, he 
established his point by tests with methyl cyanide which on oxidation 
liberates toxic substances. In his tests a mouse which recovered from 
a dose of 0.5 mg. of methyl cyanide per gram of weight, after a 
month's feeding with small quantities of alcohol in the food, quickly 
succumbed to a dose of 0.2 mg. Furthermore, Hunt found that the 
ethereal sulphates were relatively strongly increased, 3 to 50 per cent., 



36 THE ALCOHOL GROUP 

under alcohol feeding, indicating failure of complete oxidations. 
This discovery, together with Edsall's observation of unoxidized 
phenol in the urine of chronic alcoholics, may also be explained as 
indicating injury to liver metabolism under alcohol. 

12. The elimination of alcohol. — Alcohol is practically all oxidized 
in the body as shown by the calorimetric determinations of Atwater, 
except when excessive quantities are introduced. Of the remaining 
alcohol a trace only is eliminated by the lungs as shown by Cushny, 
and the remainder is excreted through the kidney. 

The excretion of alcohol by the kidney, especially when excessive 
amounts are taken, leads to certain cumulative effects which produce 
irritation. This produces a tendency to nephritis, which interferes 
with the normal functions of that organ. 

13. The effects of repeated use of alcohol on tolerance, and 
on the germ-plasm and fertility. — Alcohol, like a number of the al- 
kaloids, when used repeatedly leads to the production in the tissues of a 
degree of tolerance. The body protoplasm acquires an increased 
power of oxidation and becomes less responsive to the drug. This 
accounts for the ability of a chronic user to consume such large 
quantities of alcohol without intoxication. Unfortunately these 
protoplasmic changes are associated with an unconquerable desire 
for the alcohol. The nervous tissue gets into such a state that the will 
power is no longer able to withstand the craving, and the individual 
consumes an excessive amount of alcohol. The moral and ethical 
side of this question is emphasized in voluminous literature. 

One of the most important changes produced in the body by alcohol 
is that on the germ-plasm. Both man and animals show a great 
decrease, not only in fertility, but in the number of normal offspring. 
Hodge has bred dogs from alcoholic parents in comparison with 
normal dogs and finds that the alcoholics show an average fertility 
of one-half, namely, 50 per cent. Of the young produced by normal 
parents an average of 90.2 per cent, were normal young. In alcoholic 
dogs this percentage of normal offspring is reduced to 17.4 per cent. 
Hodge quotes an instance of a study made on human parents showing 
that the number of viable children from alcoholic parents was 17 
per cent, as against 88.5 per cent, from normal parents. The alcoholic 
families of both man and dogs produce a high percentage of defective 
and deformed offspring, many of the young in fact being born dead. 
The strength and development of the human embryo are dependent 
upon two factors, inheritance from the germ-plasms and nutrition 
during embryonic life. That alcohol influences the inheritance factor. 



SUMMARY OF EFFECTS OF ALCOHOL 37 

through the father as well as through the mother, is indicated by the 
number of deformed and defective children born of parents of which 
one alone is alcoholic. Of the children born many are non-viable, 
that is, for one reason or another they are unable to take nourishment 
and do not develop normally. Possibly these defects are due to 
failure of full development of some internal structure. 

14. The alcohol habit and disease. — Physicians, as well as lay- 
men, now take into account the habit-forming tendency produced by 
alcohol. "With its repeated use the tissues not only acquire power to 
oxidize and dispose of the alcohol, but there results a change which 
leads to a craving that cannot be satisfied. It is this factor which 
often leads to a rapid disintegration of an otherwise apparently 
strong and healthy individual. Through its effects on the defensive 
qualities of the blood, i.e., the phagocytes and the anti-toxins pro- 
duced by them, as well as because of the general changes in the effi- 
ciency of the circulatory apparatus, the profound changes in the 
metabolism of the liver, the tissues in general are rendered non- 
resistant to the invasion of disease. Germs which otherwise would 
be successfully combated and eliminated from the body are able to 
gain a foothold. This factor was especially emphasized by the obser- 
vations of Hodge on alcoholic dogs. An invasion of disease into his 
experimental kennels resulted in the death of several of his alcoholic 
dogs, whereas the normals recovered after relatively light attacks. 
Similar observations have been made at the various clinics on men. 
In quite recent years it has become a well-established fact that the 
excessive users of so mild an alcoholic drink as the Munich beer, are 
rendered more liable to disease and show a higher death rate. 



IV. 

Condensed Summary of the Effects of Alcohol on the Human 

Organism. 

Alcohol is a local irritant, acting on the skin of the mouth 
and on the mucosa of the stomach. It produces secondary reflex 
effects when so applied, some of which are quite favorable. When 
introduced into the general system, alcohol produces a narcotic effect, 
especially on the nervous tissues. It diminishes the activity of the 
cortex in its most complex relations, as shown by decrease in intellec- 
tual power, emotional control, and will power. The lower centers 
of the central nervous axis are temporarily released from the inhibitive 



38 THE ALCOHOL GROUP 

control of the cerebral cortex, but later are depressed in function and 
ultimately paralyzed. Alcohol diminishes the efficiency of the vital 
organs, like the heart, blood vessels, the blood, and their nervous 
mechanisms, in certain cases with an initial but evanescent stimula- 
tion. In acute use it favors the reflex increase of the digestive secre- 
tions, but with a decrease in the amount of enzyme present in a given 
quantity of secretion. It also diminishes the digestive efficiency of 
the enzyme. Alcohol produces irritation and ulceration of the stomach 
after prolonged use, especially in the concentrated form. It also 
diminishes the motility of the stomach and the intestine. It inter- 
feres with the metabolism of the body, especially with the oxidations 
in the liver of the by-products of protein and nuclear metabolism. It 
tends to produce local inflammation in the kidney. It leads to the 
formation of the alcohol habit, and, in prolonged and chronic use, 
changes the germ-plasm and thereby diminishes both fertility and the 
viability of offspring. It breaks down the resistance of the body to 
disease by destroying the efficiency of the phagocytes, and leads to 
premature death of the individual. 



THE ANESTHETICS. 

CHAPTER III. 

ETHER 

I. 

Historical. 

Members of the group of anesthetics are characterized by the 
physical property of volatility, also by the physiological property 
of producing unconsciousness, and therefore loss of pain without 
any great danger to life. They have proven an invaluable boon to 
suffering humanity in their use in surgical anesthesia. The anesthetic 
properties of ethyl ether were introduced to the public by the activities 
of Morton in Boston in 1846. Chloroform was introduced the next 
year, 1847, by Simpson at Edinburgh. Nitrous oxide soon after 
came into popular use for periods of short anesthesia. In determining 
priority it appears that the anesthetic action of both nitrous oxide 
and of ether had previously been discovered, and had been used in 
isolated cases; but for one reason or another this knowledge had 
not become public property. Jackson demonstrated the anesthetic 
power of ether in 1841, and Long first used ether in surgery in 1842. 
But the honor of introducing ether into public use really belongs 
to Morton, not as its discoverer, but by virtue of his success in 
the public demonstration of its surgical value. 

It is now well known that even the ancients produced a degree 
of anesthesia or insensibility to pain in surgical operations. They 
used alcohol, some plant infusions, and in some cases a degree of 
asphyxiation, thus securing carbon dioxide anesthesia. But the intro- 
duction of drugs as a regular routine in relieving pain in surgical 
operations dates from the popular demonstration of ether in Boston 
by Morton in 1846. 

The anesthetics, by virtue of their great volatility and ready 
absorption by the tissues, are peculiarly adapted to surgical purposes. 
Inhaled, they come into intimate contact with a relatively large 
absorbing surface, the pulmonary capillaries. They quickly pass 
into the blood and are as quickly distributed throughout the body. 



40 ETHER 

On the other hand, their elimination is by the lungs, a process which 
is at first equally rapid and efficient. Volatility with ready absorp- 
tion and elimination gives an immediate and advantageous control 
of the degree of narcosis quite impossible with non-volatile drugs that 
must be introduced by the slow process of gastric and hypodermic 
absorption, and eliminated by the even more retarded paths of general 
excretion. 

The relative action and safety of ether and chloroform have 
aroused a great amount of investigation throughout the surgical 
world. In Europe chloroform gained the greater favor, and has 
been used most extensively down to comparatively recent years. In 
America ether has been in greater favor and, at the present time, is 
used almost exclusively, except where it is contraindicated in special 
surgical cases. It is difficult to determine the relative danger of the 
two and our statistics depend almost entirely on figures derived from 
hospitals where conditions are most safe for its successful adminis- 
tration. Statistics from St. Bartholomew's from the years 1875 
to 1890 show a death list for: 

Chloroform, in 18,526 cases, 13 deaths, 1 death to 1,502 

Ether in 8,491 " 3 " 1 " " 2,830 

Gas and ether in 12,941 " 1 death, 1 " " 12,941 

In the cases collected by Julhard, the death-rate was: 

Chloroform 1 to 3,258 for 524,507 cases 

Ether 1 to 14,987 for 314,738 cases. 

The above figures indicate that the chloroform is about five 
times more fatal than ether, but that neither is especially dangerous. 
The eases do not, however, take into account the toxic influence on 
the organs produced by the anesthetic, such as develop secondary 
changes that may lead to death at some later period. Chloroform 
is generally recognized as much more dangerous from this latter 
point of view. 

II. 

Outline of the General Action of Ether. 

i. Stages of anesthetic effects. — Since ether and chloroform are 
used primarily for the production of anesthesia, it will be desirable 
to present at once the successive general stages recognized in the 
process of anesthetizing. These stages have been described by numerous 



STAGES OF ETHER ANESTHESIA 41 

writers, and somewhat variously classified. However, four phases of 
action may be recognized as described in the changes in the general 
functions of the whole body. These are: 

1. The excitement stage, 

2. The intermediate stage, 

3. The surgical anesthesia stage, 

4. The toxic stage. 

The excitement stage is characterized by the presence of profound 
reflexes which are induced by the action of the ether on the mucous 
membranes of the respiratory tract. These lead to irregularities 
and some acceleration of the respiration, and often to violent cough- 
ing. Kespiration may occasionally be completely inhibited for several 
seconds, even producing considerable cyanosis. These periods are 
followed by deep and spasmodic respiration in which deep draughts 
of relatively saturated ether vapor are drawn into the lungs. There 
is reflex irregularity of heartbeat with considerable quickening of 
the pulse. There is a tendency to emotional states coupled with mental 
incoordination. In the late stages of this period analgesia is produced. 

The intermediate stage is usually short, but is associated with 
mental delirium, often strong muscular contractions or even spasms. 
There is great irregularity of respiration characterized by deep in- 
spiratory gasps. The cutaneous blood vessels are dilated, and narcosis 
and unconsciousness quickly supervene. 

The stage of surgical anesthesia is characterized by complete loss 
of pain sensations, complete relaxation of the voluntary muscles, and 
loss of general muscular reflexes. The breathing becomes regular as 
in a deep sleep, the pulse is regular, somewhat rapid, and the blood 
pressure medium. The light reflexes are lost and the pupil widely 
dilated. The corneal reflexes are present in light anesthesia, dropping 
out in the deep stages, a valuable indication of the degree of anesthesia. 
The temperature of the body is lowered, due to the greater dilation 
of the cutaneous blood vessels and to lowered metabolism. The 
anatomic mechanisms are still intact and respond to reflexes in the 
usual way, except in the very deep and profound anesthesia. 

The toxic stage or danger stage is indicated by a marked slowing 
followed by complete cessation of respiration. The blood pressure 
becomes low with paralysis of the vasomotor center, the heartbeat is 
weak from direct muscular anesthesia. The respiratory center often en. 
tirely ceases; even when the blood-pressure is relatively high, the heart 
will continue beating for some seconds. In mammals the circulation 
is kept up until the blood becomes strongly cyanotic, at which stage 



42 



ETHER 



there usually occurs a series of respiratory gasps in response to the 
direct effects of the highly venous blood on the respiratory centers. 

TABULATION OF THE CHARACTERISTICS OF THE STAGES OF 
ANESTHESIA. 

r coughing 

respiration accelerated 

pulse quickened 

vertigo 
-< occasional sharp reflex cardiac inhibition 

emotional tendency 

incoordination 

dilated pupil 
L analgesia 



1. Excitement stage 



2. Intermediate stage 



delirium 

muscular spasms 
respiratory irregularity 
dilated blood-vessels 
narcosis 
unconsciousness 



' pain sensations lost 
muscular relaxation with loss of muscular reflexes 
regular breathing 

regular pulse with medium blood-pressure 
3. Surgical anesthesia stage -{ light reflexes lost, pupil widely dilated 

corneal reflexes present in lighter stages 

absent in deeper 
temperature lowered by greater loss of heat 
I alimentary reflexes present except in deepest stage 



4. Toxic stage 



f respiratory center becomes slower and ceases 
blood-pressure very low with paralysis of the vaso- 
motor center 
heart weak from direct muscular anesthesia 



III. 

The Details of the Action of Ether. 



i. The action of ether on the central nervous system. — The 
changes in the function of the central nervous system are the ones 
most important to surgical anesthesia, and many of the details have 
already been given in the summary above. From this list it is obvious 
that the narcosis is a descending one. It begins with the suppression 
of function of the higher or cortical centers, and is closed with the 
loss of function of the great vital centers in the medulla. There is 
an evident similarity of action to that produced by alcohol, also to 
that produced by chloroform as will appear later. 

Ether narcosis is preceded by a short stage of stimulation or 
accelerated function. Waller has demonstrated this point by a direct 



ETHER OX THE NERVOUS SYSTEM 43 

study of nerve fibers. He determined the volume of the nerve impulse 
as measured by the action current which was given in response to a 
constant stimulus. This he found to be sharply increased at the 
initial stage of the action of ether. If this principle were accepted in 
general it would account for a number of phenomena noted in the 
stimulation stage in anesthetizing. However, many of the phenomena 
can also be accounted for largely on the basis of descending nerve 
narcosis, the principle considered in the study of alcohol. 

Many of the effects, when ether is first inhaled, are produced, not 
by the action of the ether on the central nervous system, but by 




Fig. 6. — Ether vapor on nerve irritability. A muscle nerve preparation is so ar- 
ranged as to subject the nerve only to ether vapor, which was applied between the 
arrows. Electrical stimulation at 10 second intervals. The first two contractions of 
the muscle are normal. The successive five contractions during the application of 
ether vapor. Slow recovery occurs on the removal of the vapor by a stream of fresh 
moist air through the apparatus. New tracing by Wallace. 



reflexes started by the local irritant action on the mucous membrane 
of the mouth, nasal cavity, and respiratory tract. Some anesthetists 
avoid this action in hypersensitive individuals by a preliminary nar- 
cotic, by cocaine sprayed into the upper portion of the respiratory 
channel, or by nitrous oxide gas. 

In the deeper stages of anesthesia, sensory stimuli no longer arouse 
the more complex centers of the central nervous system. Certain 
centers in the spinal cord, and especially in the medulla, are still 
capable of executing reflexes. Experiments of Bernstein indicate 
that local anesthesia of the spinal cord produces a block for sensory 
nerve impulses for spinal nerves of the anesthetized region, whereas 
reflexes still occur through the anesthetized region upon stimulation 
of sensory nerves of a non-anesthetized region. This indicates that 
the block to reflex nerve impulses occurs primarily in some of the 
sensory connecting links, rather than in the motor cells of the cord and 
brain stem. In the deeper anesthesia the motor cells also lose their 
irritability. 

The nerve centers in the medulla respond to reflex stimulation 
long after the cerebral cortex is narcotized, and after sensory reflexes 



44 ETHER 

through the cord are lost. In animal experimentation the stimulation 
of the various sensory nerves, as, for instance, the sensory fibers of 
the vagus, produces, not only respiratory effects through the medul- 
lary center, but cardiac and vasomotor effects through their respective 
centers located in the same region. 

The retention of reflex irritability under ether anesthesia is of 
great surgical importance. It permits reflex stimulations during 
operations that may be, and generally are, important factors in pro- 
ducing the undesirable condition of shock. In recent practice certain 
accessory drugs, i.e., urea, quinine, or novocain, are being used to 
block the course of sensory nerve impulses, thus eliminating the un- 
desirable reflexes. 

2. The action on the respiratory center. — In the excitement and 
intermediate stages the respiratory center undergoes great change, 
chiefly due to secondary stimulations developed by local peripheral 
irritation. In the toxic stage these cells are directly affected and 
are markedly depressed, respiration ultimately ceasing from loss of 
function of the cells of the respiratory center. Eecovery of the 
irritability of the respiratory center in ether paralysis is always 
possible so long as there is a considerable amount of blood-pressure, 
a factor that has been emphasized by Dixon. This is one of the chief 
points in favor of ether versus chloroform. Anesthesia so deep as 
to suspend the function of the respiratory center rarely causes a 
fall of blood-pressure of more than 50 or 60 per cent., usually much 
less. Artificial respiration will, therefore, generally recover the case. 

3. The action of ether on the circulatory system and on blood- 
pressure. — The blood-pressure is maintained at a rather high level dur- 
ing ether anesthesia. Just at the beginning of the action of ether the 
blood-pressure rises slightly, i.e., during the stimulation stage, a 
change that is chiefly secondary in character. Occasionally there 
may be a reflex fall of pressure, see the heart action discussed below. 
In surgical anesthesia the blood-pressure is slightly below normal, 
though generally strong and effective. At death from ether the pres- 
sure falls slowly until the respiratory center ceases, then it usually 
drops rapidly to 20 to 30 per cent, of the normal. The early general 
pressure fall is followed by a secondary or asphyxial rise of variable 
amount, then a final sharp fall to approximately zero. 

4. The action of ether on the heart.-AEther produces changes 
in the heartbeat both by direct action on the heart muscle and 
through the ne rvou s mechanism.^/ The first effects on the heart are 
reflexes which arise from the irritant stimulation of portions of the 



ACTION OF ETHER ON THE HEART 45 

respiratory tract. Occasionally there will be a complete inhibition of 
the heart following the first two or three whiffs of ether. This 
usually lasts for only a moment, after which the heart resumes its 
beating with the usual vigor. In the intermediate stage, as the 
ether is distributed through the system, there is generally a slight 
acceleration of the heartbeat from direct muscular stimulation. In 
the late toxic stages the heart ceases to beat also from direct muscular 
action. These facts can be beautifully illustrated by the laboratory 
methods for studying the isolated heart, f The perfused frog's heart 
almost always shows an appreciable acceleration in rate when a 




Fig. 7. — The action of ether on the isolated heart of the dog when perfused 
through the coronary arteries, 2 per cent, hy volume in Ringer-hlood solution. The 
composition of the Ringer's solution was NaCl 0.9 per cent. + KC1 0.042 per cent, -f- 
CaCl 2 0.026 per cent. Time in 5 second intervals. New tracing by Kruse, Boutwell, 
and Heldt. 



weak ether solution is used. If the solution is made stronger then 
the acceleration is followed by a marked slowing, often by complete 
stopping. "With still stronger solutions slowing and stopping occur 
at once.\ With slowing of the frog's heart there is a decrease in the 
amplitude of the contractions and a dilation of the heart chambers. 
Undoubtedly these are direct muscular effects. Isolated strips of 
turtle's heart muscle exhibit similar phenomena, the ventricle becom- 
iDg slower and weaker, and the sinus also losing its waves of tonic 
contraction. The isolated mammalian heart also shows a characteristic 
picture of anesthesia, as does the heart studied in the complex of the 
body. Leo Loeb studied the effect of ether on the isolated mammalian 
heart, showing that 0.4 per cent, ether in solution in the blood leads 
to a stoppage of the rhythm. 

5. Ether on the blood vessels. — In the stimulation stage of ether 



46 



ETHER 



anesthesia there is a marked flushing of the skin, an effect that is a 
secondary reflex response to the local sensory stimulation of the 
respiratory tract. However, this stage is quickly followed by the 
direct systemic action of the ether on the blood vessel walls and on 
the vasomotor center of the medulla. The latter is lowered in its 
sensitiveness to the usual medullary reflexes, thus leading to a loss of 
vascular tone. The decrease in peripheral resistance to the blood 




Fig. 8. — Ether, 4 per cent, solution in physiological saline, on the isolated cardiac 
muscle of the terrapin. Time, 5 seconds. New tracing by Summers. 

flow results in most of the fall of blood-pressure noted under ether. 
The vasomotor center, fortunately, does not completely lose its reflex 
irritability, in fact this irritability is only slightly diminished to the 
great mass of autonomic reflex stimulations. 

The peripheral vascular actions of ether are not uniform throughout 
the whole body. Along with the marked flushing of the skin, Kemp 
has shown that in the dog the blood vessels of the kidney are con- 
stricted. Of course such a constriction leads to an interference with 
the secretion of urine, and may produce complete anuria. It is 
possible that this renal action is due to the direct local action of 
the ether during excretion. The kidney is an important organ in 
the elimination of ether, especially during surgical anesthesia, when 
the concentration in the blood is greatest. The local concentration 
during excretion leads to local irritation and therefore inflammation, 
mild nephritis, or in prolonged anesthesia marked nephritis will 
result, a condition that is later associated with albuminuria, which is 
its characteristic symptom. 



ETHER ON MUSCLE 47 

6. Action of ether on voluntary muscle. — It is easy to demon- 
strate by laboratory experiments that voluntary muscle is anesthetized 
as well as is nerve. If a muscle-nerve preparation be suspended in a 
moist chamber and the nerve alone be surrounded by ether vapor, the 
nerve shows a decreased irritability as judged by the response of 
the muscle to maximal and minimal stimuli. If the muscle alone 
be subjected to ether vapor it also shows a decrease in irritability 
lasting for some moments after the ether vapor is replaced by pure 
air. Ether narcosis of the nerve is preceded by a brief and slight 
increase in irritability, a fact which has not been shown for muscle. 

7. Action of ether on the alimentary canal. — The effects of 
ether on the alimentary tract are also twofold, namely, systemic and 
local irritant with its corresponding reflex changes in function. In 
ordinary procedure the most marked stimulations occur in the mouth 
and upper respiratory tract, the reflex effects of which have already 
been discussed in relation to respiration and circulation. Important 
alimentary reflexes are produced through the various secreting glands 
connected therewith. The salivary glands, for instance, are markedly 
stimulated and a marked increase in the secretion of saliva follows. 
The smaller glands of the mouth and of the walls of the bronchial 
tubes also have their secretions increased. The movements of the 
alimentary canal are depressed by ether, especially in the deeper 
stages where they may be stopped altogether. But " Ether can be 
given sufficient to prevent any movements of skeletal muscle without 
interfering with the alimentary canal " (Cannon). 

Meltzer has recently called attention to the possibilities of anes- 
thetizing per rectum. While ether is absorbed in this locality it is 
not considered a very favorable method of anesthetizing, owing to 
the high local irritant action of the anesthetic. No specific effects of 
ether on the efficiency of the alimentary tract as a digesting mechan- 
ism have thus far been shown. 

8. The absorption, distribution, and excretion of ether. — Over- 
ton and Meyer have advanced theories accounting for the absorption 
of ether and chloroform. Their view is that the anesthetics produce 
their characteristic action by virtue of great solubility in the cell 
lipoids. The fats and fatty compounds of the cells dissolve the ether 
and this changes the physical-chemical constants of the cell protoplasm, 
thereby interfering with its normal function. Such tissues as the 
nerve cells, which have a high content of lecithins, etc., would by this 
theory receive a greater quantity of ether than other tissues, as for 
example, the skeletal muscles. This theory furnishes a good working 



48 ETHER 

hypothesis, though there is considerable evidence against its complete 
acceptance. 

In any case the ether markedly interferes with the metabolism 
of the cell protoplasm. Heat production is diminished and nitrogenous 
metabolism also. That the protoplasmic structure is to some extent 
disorganized is shown by the degenerative changes, fatty infiltrations, 
etc., which follow deep anesthesia. The kidney, the heart, the nerves, 
all have been shown to undergo varying degrees of fatty degeneration 
following surgical anesthesia. This is evidence of the degeneration 
of protoplasm, and of the fact that the drug is toxic in a chemical 
sense as well as in a physical. 

Ether is primarily eliminated by the same channel by which it 
enters the body, namely, the respiratory tract. Its great volatility 
favors its elimination from the body by this channel. Complete 
elimination takes place only very slowly, and ether can be detected 
in the breath for many hours after only a mild inhalation. Elimina- 
tion also takes place through the kidney where ether is excreted with 
the urine. The slow passage of the urine along the tubules favors 
irritant action of ether on the renal cells, thus producing inflamma- 
tion and fatty degeneration, i.e., nephritis. 

IV. 

Condensed Summary of the Action of Ether on the Body. 

Ether is a most reliable surgical anesthetic. It produces complete 
loss of consciousness, is relatively free from danger, and permits of 
rapid recovery when the drug is eliminated. The stages of anesthesia 
are (1) an excitement stage characterized by accelerated respiration 
and heartbeat, slight rise of blood-pressure, a local irritation of the 
respiratory tract with reflex dilatation of the pupil, a confusion of 
mental impressions. This stage is followed by (2) an intermediate 
one in which there is mental incoordination, a tendency to muscular 
reflexes that are uncoordinated in character, irregularity of respira- 
tion, analgesia, and finally complete unconsciousness, passing over 
into the third stage of surgical anesthesia. This is characterized by 
complete muscular relaxation, insensibility to pain, loss of muscular 
reflexes, regular respiration and heartbeat, an even blood pressure, loss 
of eye reflexes in the deep stages, but retention of the function of the 
medullary center. The final or toxic action of the drug is charac- 
terized by slow respiration with final stoppage, slight fall of blood- 



SUMMARY OF ACTION OF ETHER 49 

pressure with slow and weak heart, which continues to beat for some 
moments after respiration ceases and before final death. Ether 
produces the most profound effects on the nervous system, but prac- 
tically all the other tissues are anesthetized. The heart is reflexly 
inhibited, but finally slowed and paralyzed by direct action. > The 
glandular tissues are reflexly stimulated to secretion, especially the 
salivary glands and the glands of the respiratory tract, with later 
depression. The kidney is directly and locally irritated, with a 
tendency to vascular constriction and suppression of urine, followed 
in the after period by albuminuria. Local actions in the lungs are 
irritation with a slight predisposition to inflammatory processes. 
Fatty degeneration may follow as a sequence in the liver, the kidney, 
and the heart. On the whole, ether is relatively safe, about four to 
five times safer than chloroform. 



CHAPTER IV. 
CHLOROFORM 

I. 

Details of the Action of Chloroform. 

i. Stages of anesthetic effects. — With chloroform, as with ether 
there are well-marked stages of effect during the production of 
anesthesia. These stages are characterized by very definite symp- 
toms which are similar in character to those produced by ether. 
Chloroform is much more toxic than ether and must be administered 
with its vapor well diluted with air. On this account the excitement 
stage and also the intermediate stages as described for ether are very 
much foreshortened with chloroform. 

It is generally stated that the local effects of choloroform are 
less irritant than in the case of ether. However, this difference does 
not preclude the local stimulations of the mucous membrane of the 
respiratory tract and the production, therefore, of all the local reflexes 
described for ether. These, it will be remembered, are interference 
with the respiratory rate and depth often with a temporary complete 
inhibition of respiration, increased reflex secretion of saliva, and 
marked irregularity of the circulation due primarily to reflex cardiac 
inhibition. A few deep whiffs of concentrated chloroform vapor at the 
beginning of its inhalation often lead to complete but temporary 
inhibition of respiration. 

In surgical anesthesia the greater intensity of action of chloroform 
is still operative, therefore there is a much narrower margin between 
the light and the deep stages, and between the anesthesia and the 
toxic stage. It is evident that slight variations in the proportion of 
chloroform vapor and of air will produce relatively great variations 
in the degree and intensity of anesthesia. In short, it requires a 
greater degree of skill on the part of the anesthetist to maintain a 
uniform and safe chloroform anesthesia. The percentage of saturation 
of chloroform vapor in the inspired air has been investigated by 
Rosenfeld. 1 His results on rabbits are given in part in the following 
table : — 

1 Rosenfeld, Max, Archiv fur Pathologie und Pharmakologic, Vol XXXVII., 
p. 52, 1896. 

50 



ON THE CENTRAL NERVOUS SYSTEM 51 

The Rapidity of Onset and Degree of Chloroform Anesthesia in Rabbits in Re- 
lation to the Percentage of Concentration of Chloroform in the Air. 



Exp. 


Per cent, by 


volume of 


Time before 


complete anesthesia, and notes. 


No. 


chloroform 


vapor 






6 


0.54—0.69 


No anesthesia in 1 hr. 


Reflexes present, 






43 min. 


Heart rate depressed. 


5 


0.93—1.01 


Anesthesia 


in 40 min. 


Respiration regular for 4 hrs. 


4 


0.93—1.01 


te 


" 53 " 


Heart rate accelerated. 


3 


1.16—1.22 


ee 


" 31 " 


Respiratory failure in 1 hr. 56 min 


2 


1.41—1.47 


te 


" 36 " 


Heart markedly depressed. 
Respiratory failure in 1 hr. 13 min. 


1 


1.63—1.65 


te 


" 11 " 


Respiratory failure in 45 min. 



2. The action of chloroform on the central nervous system. — 
With chloroform as with ether the narcosis of the nervous system 
is in a descending direction. The higher cortical functions pass 
through a very slight and brief stimulation stage, followed by a 
complete, but temporary loss of function. The suspension of func- 
tion involves, first the cerebral cortex and the great tracts of the 
sensory and the association centers, later the spinal reflexes, and 
finally the great vital centers of the medulla. Many of the early 
effects produced by chloroform are accomplished through variations 
in the reflexes of different portions of the nervous system. 

Keflexes that have their origin in primary stimulation of sensory 
surfaces of the respiratory tract can, to some extent, be depressed 
by previous treatment that lowers the sensibility of the cutaneous 
nerve endings, as for example by cocaine spraying or previous appli- 
cation of other drugs with local depressant action. 

Of the reflex effects the most profound are those which react 
through the respiratory center and through the cardiac inhibitory 
center. Some animals, as for example the rabbit, are especially 
sensitive in this regard. A whiff of chloroform vapor is often sufficient 
to inhibit respiration in the rabbit for many seconds. Occasional 
clinical experiences of the anesthetist show that a certain percentage 
of individuals of the human species also respond more completely to 
these local stimulations. In the later stages of chloroform anesthesia, 
the vital centers which are involved in the early reflex responses are 
narcotized by the direct action of the chloroform on the nerve cells. 
If the narcosis be deep then the sensitiveness of the centers to the 
usual sensory stimuli is lowered and the responses are correspondingly 
diminished. 

The danger stage of anesthesia depends chiefly on paralysis of the 
respiratory center. As a rule the irritability of the respiratory center 
can readily be recovered if the anesthetic has not produced too great 



52 



CHLOROFORM 



a fall of blood-pressure. However, chloroform has a profound effect 
upon blood-pressure, and, unfortunately, tends to a marked lowering 
of pressure at a time somewhat preceding the paralysis of the 
respiratory center. On this account, deep chloroform anesthesia is 
much more dangerous than that with ether. Artificial respiration 



\i\ 




Rate 48 



Rate 96 



a 

1 l I 



45 



90 



C 

I I I I I 



36 




79 



d 

i i i 



i 



42 



90 



33 




78 



/ 

I i i 



Fig. 9. — The mild influence of chloroform on blood-pressure, heart rate, and on 
respiration. The respiratory and cardiac rates are indicated on the tracing. Between 
the successive portions indicated from a to f there have been omitted 10, 10, 15, 40, 
and 100 seconds, respectively. New tracing by Gullion. 



will often suffice to recover activity of the respiratory center when its 
function has been lost by a temporary toxic stage. This recovery 
is, however, much more difficult to attain than in the case of ether. 

3. The action of chloroform on the circulatory system, — blood- 
pressure. — Chloroform tends to lower blood-pressure. In mammalian 
experimentation one rarely notices any initial rise of blood-pressure. 
The fall of pressure is accompanied, perhaps caused by an initial 
reflex slowing of the heart. Deep anesthesia is accompanied by 
narcosis of the musculature, not only of the heart, but of the 
arterial system as well. During surgical anesthesia the blood-pressure 
is considerably below that of the normal. If the anesthetic is pushed 
far, then there will be a marked and sudden fall of blood-pressure, 
with a slow and weak heartbeat and ultimate death. In mammals, as 
a rule, the respiratory center ceases its action before paralysis of the 



CHLOROFORM OX BLOOD-PRESSURE 53 

heart is complete. This, however, depends upon the rapidity with 
which the chloroform is given. 

4. The action of chloroform on the heart. — The first effect of 
chloroform on the heart is a reflex slowing produced by the local 
irritation of the sensory nerves of the mouth and naso-pharyngeal 
region. This slowing usually passes away after the anesthetic induces 
its systemic effects. During the initial systemic action there is a brief 




Fig. 10. — The influence of chloroform on the contractions of the isolated heart of 
the cat. The chloroform was in Ringer-hlood solution, 0.03 per cent, by volume. 
There is some lag before the chloroform solution reaches the heart tissue, also a slight 
mechanical displacement at the time the solution was turned on. Time, in 5 second 
intervals. Perfusion as marked. New tracing by Boutwell, Heldt, and Kruse. 

period of slight irregularity of the heart accompanied by periods 
of accelerated rate. 

'Chloroform has a marked depressing action upon the functions 
of the heart muscled In deep anesthesia this depression accounts 
in large measure for the slow and weak pulse. Rhythmic beating 
strips of heart muscle cut from the ventricle of the terrapin respond 
very delicately to chloroform anesthesia. The amplitude is quickly 
diminished and the rate rapidly slowed and inhibited after suffi- 
cient vapor is used. } ( If the anesthetic reaches the stage of complete 
inhibition of rate then the rhythm is restored only after a long latent 
period.'l Chloroform and ether are usually in sharper contrast in this 
respect than shown in Figures 8 and 11. 

The mammalian heart is also very susceptible to chloroform vapor, 
presumably on account of the muscular effects of the drug. Isolated 
mammalian hearts show a diminution in rate and a great decrease 
in the amplitude when weak solutions of chloroform are added to 
the perfusing liquid. When simultaneous cardiograms are made from 



54 CHLOROFORM 

the auricle and from the ventricle of an experimental mammal these 
effects on the rhythm and amplitude are shown in fine contrast. 
Cushny, and Gottlieb and Meyer, have published figures on this 
point. Cushny, especially, has demonstrated a more marked influence 
on the excursions of the auricle than on the ventricle. Ventricular 
contractions will be medium strong and vigorous at a time when the 
auricular contractions are reduced to a minimum. 

The more profound stages of chloroform suspension of function of 




Fig. 11. — Chloroform 0.1 per cent, in physiological saline on the rhythm of the 
ventricular muscle of the terrapin. The marked decrease in amplitude and rate is 
characteristic. This strength of chloroform will often completely inhibit the rate 
within five to ten seconds. Compare with Fig. 8 showing the effect of ether. Time 
in 5 seconds. New tracing by Summers. 

the cardiac muscle do not immediately destroy the vitality of the 
tissue. The function can be reestablished, though with much greater, 
difficulty than with ether. However, a pronounced toxic effect upon 
the protoplasm follows after such deep stages. A certain proportion 
of the heart protoplasm is killed, as indicated by the fatty degenera- 
tions which follow after a lapse of two or three days. These degenera- 
tions are in fact of great vital importance, hence very deep chloroform 
narcosis is to be avoided under all circumstances. 

5. Action of chloroform on the blood-vessels. Following the 
first few inhalations of chloroform vapor there is a reflex vaso- 
dilation shown by the flushing of the skin. This stage is quickly 
followed by a direct systemic action of the drug on both the vaso- 
motor center and the blood-vessel walls. The vasomotor center loses 
its delicacy of response to the usual stimulations, thus allowing a 



CHLOROFORM ON MUSCLES 55 

passive dilation of the blood-vessels. The smooth muscles of the 
blood-vessel walls are directly narcotized. This leads to relaxation 
and dilation and to a corresponding fall of blood-pressure. 

Local organs are affected by the dilation of the peripheral blood- 
vessels and the fall of blood-pressure. The kidney, for example, 
is markedly affected. The dilation of the renal vessels immediately 
allows greater carrying volume of blood, though this is more 
than counterbalanced by the general fall of blood-pressure. The 
general result is that the solution of chloroform vapor in the blood 
is brought into contact with the renal tissue in relatively greater 
amount, i.e., the slow speed of the blood through the vessels allows 
of proportionately greater time for local absorption, hence the renal 
tissue is correspondingly deeply anesthetized. This is shown, in 
part, through the partial suspension of function of the kidney. In 
a word, the somewhat more sluggish stream of blood through the 
kidney is, not only in itself unfavorable to the excretion of urine, but 
is favorable to the production of anesthesia of the renal tissue, still 
further reducing the power of excretion. As chloroform is excreted 
by the renal tubules it follows that there will be a somewhat con- 
centrated action of the drug at this point. 

Other organs, such as the liver, are similarly affected. Doubtless 
this is the explanation of the tendency to fatty degeneration in the 
kidney, liver, etc., following prolonged or deep chloroform anesthesia. 

6. Action of chloroform on the voluntary muscles. — Voluntary 
muscles are directly anesthetized by chloroform. This is readily 
shown by the decrease in irritability of the muscles to direct stimula- 
tion during anesthesia. When isolated skeletal muscle is anesthetized 
with chloroform to the point of complete loss of irritability it can 
be recovered only by complete removal of the vapor and after pro- 
longed treatment with air or oxygen. The anesthesia stage for skeletal 
muscle is deeper and more profound for chloroform than for ether. 

7. The action of chloroform on the alimentary canal. — Chloro- 
form will anesthestize the tissues of the alimentary tract as it does 
every other tissue thus far examined. These effects are, as in ether, 
both indirect through the reflexes and direct. The direct effects come 
only after the chloroform is absorbed into the blood and has passed 
through the circulation. This stage is characterized by a depression 
of function, i.e., by anesthesia of the muscles of the stomach and 
intestine and by a suspension of the secretion of the digestive glands. 

The reflex effects are accomplished chiefly through the local action 
of chloroform on the naso-pharyngeal and mouth regions. These 



56 CHLOROFORM 

reflexes last only a brief time and consist in the increase in the secre- 
tion of the saliva and probably of gastric juice. The normal peri- 
stalses of the stomach and of the intestine are suppressed by chloro- 
form, though the matter has not been sufficiently investigated for full 
statements. 

8. The absorption of chloroform. — The great volatility of chloro- 
form favors its administration admixed with air by way of the res- 
piration. Though it has a relatively low solubility in water and in 
the watery content of the cells, i.e., a saturation factor of one part in 
two hundred, 0.5 per cent., still this is well above the efficient con- 
centration for anesthetic purposes. Its solubility in the cell lipoids 
also favors its absorption by the tissues. Probably, as Meyer and 
Overton have indicated, this lipoid solubility is a factor in the dis- 
tribution and relative intensity of action of chloroform on the tissue. 
This would account for its specific effects on the nervous tissue, the 
red blood cells, etc. Roaf gives good evidence to show that the re- 
actions of chloroform in the body are not entirely physical. 

Metabolism is lowered by chloroform. This is evident from the 
great diminution of the output of nitrogen as well as the lowering of 
functional activities which characterize chloroform anesthesia. Chlo- 
roform tends to destroy the protoplasmic organization ; this undoubt- 
edly is the contributing factor which leads to more or less fatty degen- 
eration after its administration. If the destruction of the tissue is 
slight, then ultimate repair occurs and no untoward effects follow. If 
the injury is marked, then fatty degeneration occurs with its chain 
of pathological disarrangements from which death will occasionally 
follow. Unfortunately these delayed effects are not always charged 
up to the primary cause, i.e., chloroform anesthesia. 

9. The excretion of chloroform. — Chloroform, like ether, is elimi- 
nated from the body by the respiratory tract and by the kidney. 
The respiratory tissue through which the chloroform vapor enters 
and in a large measure leaves, and the kidney are relatively deeply 
anesthetized. They, therefore, feel the evil effects of the anesthetic 
as expressed in degenerative changes. 

II. 

Condensed Summary of the Action of Chloroform on the Body. 

Chloroform is a widely used surgical anesthetic, comparing in value 
with ether. It produces complete loss of consciousness and a descend- 



SUMMARY OF ACTION 57 

ing elimination of function of the great divisions of the central 
nervous system. Rapid elimination and recovery follow when the 
drug is removed. The stages of anesthesia are the same as with 
ether, except that the excitement stage and the intermediate stage are 
passed over more quickly. Chloroform vapor must be administered 
with great dilution in air. Slight variations in the concentration of 
the vapor produce more profound variations in the degree of anes- 
thesia. Chloroform is several times more toxic than ether, therefore, 
more dangerous. In the danger stage there is complete loss of mus- 
cular reflexes, great weakness of the respiratory activity, slow and 
weak heart, dilated blood-vessels, and correspondingly low blood-pres- 
sure. The toxic stage is marked by a cessation of respiration through 
direct action on the respiratory center and a quick fall of blood-pres- 
sure and weak heart. Recovery of the toxic depression of the res- 
piratory center is rendered very difficult because of the associated low 
blood-pressure. [The heart is directly anesthetized, greatly slowed, 
and finally paralyzed. ) The alimentary tract is at first reflexly stimu- 
lated though slightly, and later depressed because of the direct action 
of the drug on the smooth muscle. The kidney parenchyma is directly 
anesthetized, and, to some extent, undergoes toxic degeneration follow- 
ing chloroform anesthesia. The nervous tissue responds in a similar 
manner. Fatty degeneration of the kidney, of the liver, and of the 
heart muscle characterizes the after-affects of prolonged chloroform 
narcosis. Chloroform is many times more intense in its action, there- 
fore more dangerous than ether. 



CHAPTER V. 
NITROUS OXIDE. 

I. 

Historical and General. 

The anesthetic action of nitrous oxide, N 2 0, was discovered at 
the end of the eighteenth century. It is therefore the oldest of the 
anesthetics unless one give consideration to the use of alcohol along 
this line. The action of nitrous oxide was first noted by Davy. Like 
many other valuable observations this one was not followed up, 
hence the peculiar value of this agency was not utilized until after 
the introduction of ether and chloroform. Wells in 1844 rediscovered 
the action of nitrous oxide, though again this act did not result in its 
immediate introduction into general use. 

Nitrous oxide produces anesthesia, but only when administered in 
concentrated form. This fact has led to considerable discussion of 
the nature of nitrous oxide action. It is claimed by some that the 
gas does not produce anesthesia, but instead does produce a degree of 
asphyxiation by the exclusion of oxygen. However, experiments by 
Kemp and others have shown that the nitrous oxide has a direct 
effect upon the nervous tissue. Kemp experimented on dogs, allow- 
ing them to breathe nitrous oxide mixed with oxygen in known con- 
centrations. He found that when an animal was anesthetized with 
nitrous oxide mixture and then allowed to breathe a mixture of nitro- 
gen and oxygen in the same proportions, it quickly recovered from 
the anesthetized condition. Kemp analyzed the gaseous content of 
the blood and thereby proved that there was sufficient oxygen present 
to maintain life, provided an indifferent diluting gas only was 
present. These experiments indicate that asphyxiation cannot account 
for the anesthetic effects and that nitrous oxide is a true anesthetic. 

II. 

The Action of Nitrous Oxide on the General Activities of the Body. 

If nitrous oxide is inhaled in concentrated form for a few minutes, 
it quickly produces a degree of intoxication followed by unconscious- 

58 



THE ADMINISTRATION OF NITROUS OXIDE 59 

ness. The early symptoms are not unlike those of alcoholic intoxi- 
cation except that a leading characteristic is that of uncontrolled 
laughter. It is this that has led to the name ' ' laughing gas. ' ' There 
is a marked lowering of response to sensory stimuli and a decrease 
in the acuteness of pain sensations. This condition is characterized 
hy a lack of coordination of the voluntary muscles and a lowering of 
the sensibility of the central nervous system in general. This stage 
is followed by complete unconsciousness in which respiration is weak 
and in which there is a tendency to dyspnea. The circulation con- 
tinues even though there oe temporary stoppage of respiration. If the 
gas is removed, unconsciousness lasts only a brief period, 40 to 60 
seconds. Kecovery is almost instantaneous, and the individual suffers 
no untoward after-effects. 

The maintenance of prolonged anesthesia with nitrous oxide is 
difficult, owing to the high concentration of the gas required. How- 
ever, for brief operations, the nitrous oxide has proven a valuable 
anesthetic to be recommended, because of the ease of application 
and because of the lack of danger in its use. Practically no instances 
of death have been recorded which are attributable directly to the 
anesthetic. Its freedom from danger makes it invaluable for such 
operations as the extraction of teeth or for minor surgical operations, 
but its use has been largely restricted to dental work. 

This gas has no characteristic special actions in the body. Such 
symptoms as occur other than general anesthesia can be largely 
attributed to the disturbance of the respiratory balance. Partial 
anesthesia produces in the body secondary physiological effects 
as detailed in the discussion of the reactions from ether and 
chloroform. 

Nitrous oxide responses show a large percentage of disturbance 
of this type. There is, therefore, a marked rise of blood-pressure, 
increase of the heart rate, disturbances of the respiration rate, etc. 

III. 

The Administration of Nitrous Oxide. 

The surgical administration of nitrous oxide is best accomplished 
with a controlled admixture of gas with pure oxygen. This mixture 
is secured by a mechanical apparatus, of which there are several de- 
vices in use in various institutions. With such an apparatus as that 
invented by Hewitt it is possible to administer nitrous oxide of any 
concentration. His apparatus contains three chambers, nitrous oxide 



60 



NITROUS OXIDE 



in one, pure oxygen in one, and from these cylinders mixtures can be 
made in any proportion in the third chamber. A close fitting face 
mask is connected by means of a wide tube with the chamber con- 
taining the mixed gas, from which inhalations take place. However, 
the later forms of apparatus have a rubber bag attached to the mask 




Fig. 12. — Application of Hewitt's nitrous oxide and oxygen apparatus in surgical 
operation. After Hewitt. 



(which is preferable), or to a side tube on the connecting tube. The 
inhalation of external air is controlled through a side valve. 

In practice it is best to fit the mask and then allow the patient 
to breathe pure air until everything is tested. The gas bag is then 
filled with pure gas and this is breathed for from 10 to 15 breaths^ 
a quantity usually sufficient to put the patient thoroughly asleep 
without inducing cyanosis. The gas bag is then refilled with oxygen 



THE ADMINISTRATION OF NITROUS OXIDE 



61 



and gas in the proportion of 1 to 6 or 8. 1 Great variation exists in 
the individual requirements as to the percentage of gas and oxygen. 
In starting the anesthesia with pure gas, great care must be taken 
not to allow cyanosis, and if such appears during the anesthesia, the 




Fig. 13. — Chart showing nitrous oxide anesthesia associated with local infiltration 
of 1 to 400 parts novocain. The chart shows the chauges in blood-pressure and pulse 
rate during a three-hour operation for the resection of the right half of the colon. 
Bloodgood. 



practice is to allow the patient to have one or two breaths of pure 
air, thus tending to keep the blood-pressure under uniform control. 

When nitrous oxide is the only general anesthetic used, then a 
local analgesic is applied at the point of incision or wherever intense 
nerve stimulation may occur. For this purpose use novocain in 1 to 
400 parts. 2 

1 For details given in this place I am indebted to several papers by Dr. J. C. 
Bloodgood, and to personal information from Dr. J. E. Stowers, who has 
assisted Dr. Bloodgood in numerous operations. 

2 Bloodgood, J. C: Annals of Surgery, Vol. LVIII., p. 721, 1913. 



62 NITROUS OXIDE 

An illustration of the practical use of nitrous oxide gas by this 
method is given in the preceding chart, Figure 13. 

Nitrous oxide is being more and more used as a preliminary 
anesthetic to chloroform or ether. It has the effect of producing a 
quick partial anesthesia, thus enabling the patient to pass more safely 
and comfortably over the excitement stage of ether and chloroform. 
This procedure has also the economic value of reducing the quantity 
of ether required. There is practically no danger from the adminis- 
tration of nitrous oxide for brief anesthesia. Yet the disturbances 
of the circulation induced by the temporary degree of asphyxiation 
are associated with some little danger in atheroma, or in certain 
types of cardiac irregularity in which nitrous oxide is to be excluded. 



CHAPTER VI. 

CHLOKAL HYDRATE. 

I. 

Historical and Chemical. 

In 1868 Liebrich described chloral hydrate as a new hypnotic, 
since which time it has become a reliable and widely used drug for 
that purpose. Chloral hydrate is a representative of the methane 
series, with the structural formula: 

CC1 .COH.H 0. 

3 2 

( Trichloracetaldehyde ) 

The discovery of the physiological effects of this drug has led to the 
examination of numerous other representatives of the series, and 
has given us a group of drugs with general narcotic powers. In 
general they are characterized by a change in function more nearly 
resembling that in sleep and hence known as hypnotic. Chloral 
hydrate is far less volatile than either chloroform or ether. How- 
ever, it is very soluble in the body fluids, hence can be absorbed readily 
from the alimentary tract. There is a numerous series of represent- 
atives of the hypnotic group, but none have become of primary im- 
portance. Of this series may be mentioned chiefly chloral hydrate, 
urethan, veronal, and sulfonal. 



II. 

Outline of Pharmacological Effects of Chloral Hydrate. 

1. It produces a narcosis resembling deep sleep. 

2. The narcosis is characterized by a lowering of sensibility to 
stimulation with diminution of pain. 

3. There is a marked lowering of blood-pressure with slowing 
of the heart rate and a tendency to a diastolic pause. 

63 



64 CHLORAL HYDRATE 

III. 

Details of Pharmacological Action. 

i. The general symptoms. — The general symptom complex pro- 
duced by chloral hydrate is remarkably like that of natural sleep 
in a profoundly fatigued individual. There is at first inertia, drowsi- 
ness, with sluggishness in response to severe stimulation. This stage 
passes into a sleep-like stage of unconsciousness. The sensory mech- 
anisms remain irritable and the patient reacts to strong stimuli which 
may still arouse in him consciousness, unless the amount of chloral ad- 
ministered be excessive. 1 to 1.5 grams produces drowsiness with 
sleep, while a dose of 4 to 5 grams produces a profound degree of 
unconsciousness from which it is very difficult to arouse the patient, 
even with excessively vigorous stimulation. Since chloral greatly 
lowers the stimulation threshold, pain sensations are diminished. Re- 
covery from chloral is relatively slow, 4 to 5 hours after a gram dose, 
10 to 12 hours after a 5-gram dose. 

It is for these general symptoms that the members of the group 
have their special value, namely, as depressants of the central nervous 
activity. 

2. Chloral hydrate on the nervous system. — The general symp- 
toms described above are in fact nervous system effects. Chloral hy- 
drate seems to specifically depress the functional activity of nerve cell 
groups in the central nervous system. Of these groups those cells in 
the cerebral cortex are of the most profound importance since the de- 
pression of their sensibilities leads to diminished responses to the 
usual inflow of sensory impulses. The influence, however, is more 
profound in that the coordinative activities of the neurons in the cor- 
tex are depressed. 

Such responses as result in the basic nuclei of the nervous 
system from chemical or possibly hormone reactions are proven to 
be lowered. Of these nuclei those located in the medulla are the 
most important. For example, the respiratory center in the medulla 
has recently been shown by Cushny x to be lowered in its sensibility 
to carbon dioxide stimulation. It is true that this center is still 
responsive to afferent nerve stimulation while under the influence 
of chloral hydrate. The change in the nerve cells produced by 
chloral hydrate comes on only slowly and under the influence of a 
rather strong dosage. Eabbits make little response up to a dose of 

Cushny, A. R.: Journal of Pharmacology and Experimental Therapeutics, 
Vol. IV., p. 380. 



CHLORAL HYDRATE ON THE NERVOUS SYSTEM 65 

0.17 gram per kilo given intravenously. "When the dosage reaches 
0.28 gram there is a distinct fall of respiratory rate, and after 0.4 
gram a sudden fall in the rate together with an increase in the depth 
of respiration accompanied by forced breathing. Under this condi- 
tion of mild chloralization, i.e., 0.17 grams per kilo, " the reflex 
movements and general activity are very much diminished and the 
carbon dioxide production must fall in corresponding measure." 
1 ' As the dose is increased the excitability of the nerve center is so far 
reduced that it can no longer maintain the rate even under the double 
stimulus of carbon dioxide and anemia, but it continues to deepen. 
Finally its rate is reduced to one-ninth of the normal, while its depth 
is doubled. " Chloral hydrate narcosis does not, however, lower the 
rate of oxidations of sea urchin eggs. 



CHAPTER VII. 

MOEPHINE AND THE OPIUM SERIES. 

I. 
Historical and Chemical. 

The dried juice of the poppy, Papaver somniferum, contains a 
series of some twenty alkaloids of which morphine is present in 
greatest amount. The juice or milk is obtained by scarring the 
unripe seed pods. The exudate is evaporated in the open air, and the 
dried product is known as opium. Opium is produced in largest 
amount in the Asiatic countries. Turkey, Persia, East India, and 
China, and also Egypt are the great producers of opium. In recent 
years an increased quantity has been grown in Europe, and its culti- 
vation is now being introduced into the United States. The medicinal 
reactions of opium have been known since ancient time. The alkaloid 
morphine is of special interest as being the first alkaloid chemically 
isolated in pure form, 1804. 

Of the series of alkaloids present in opium, the following are the 
most important: 

Morphine C H NO 

r 17 19 3 

Codeine C HNO o 

18 21 3 

Papaverine C H NO 

r 20 21 4 

Narcotine . C H NO, 

22 23 7 

Thebaine C H NO 

19 21 3 

The percentage of the different alkaloids present in opium varies 
extremely, depending upon the country and climate, and upon the 
method of gathering and drying. Opium contains from 10 to 20 per 
cent, of morphine, the former being the average requirement of the 
medicinal drug. Opium on the market, however, may contain from 
3 to 18 per cent, of morphine, 1 to 10 per cent, of narcotine, 1 to 2 
per cent, of codeine with traces of the large number of alkaloids 
that have been isolated from this mixture. 

The chemical relationships of the opium alkaloids is complex. 

66 



HISTORICAL AND CHEMICAL 



67 



The structural formula of morphine, for example, is still in question. 
It is apparently a derivative from a hydrated phenanthrene nucleus, 
and has been given by Knorr as follows : 



OH v 

>C H 
oh/ 14 10 



0-CH 5 

I 



CH 2 

I 
KCH 3 



Codeine and thebaine differ from morphine in that the hydrogen 
of the hydroxyls is substituted by methyl, one methyl in the former, 
two in the latter alkaloid. With this substitution the change in the 
physiological action approaches that of the caffeine group, where an 
increase of methyl in the series produces the same type of physio- 
logical change in the action. The chemical relationships may be 
expressed by the following formulae: 



HO v 

>C II 
ho/ 14 10 




CH 3 



^C H 
ho/ 14 10 



-0-CH, 

I 
CH 2 

I 
KCHs 



Codeine 




CH 3 0. 

\q h 

CHsO/ 14 10 



Thebaine 

In modern synthetic chemistry a series of products have been 
built up by substituting radicals for one or more of the hydrogen 
atoms in morphine. Of these heroin is of chief importance from the 
pharmacological and therapeutic point of view. Heroin is a diacetyl 
morphine of the following formula: 



CHsCO.Ov 
CH3CO.O 



/ 



C,JI.( 



-0-CH 2 

I 
C1I 2 

, N.CH3 



Heroin 



Morphine as an alkaloid is very insoluble in water, while its 
salts are quite soluble, six per cent, or more. The salts have the 
same pharmacological action, and are generally used, the sulphate 
being official. 



68 MORPHINE AND THE OPIUM SERIES 

II. 

Outline of Pharmacological Action of Morphine and the Opium 

Series. 

1. Morphine produces a marked depression of the central nervous 
system in the descending direction preceded by slight initial stimula- 
tion. The change of greatest importance is the great decrease of 
the perception of pain. 

2. Depression of the blood-pressure with marked cardiac depres- 
sion after larger doses. 

3. An initial increase followed by marked decrease of the peri- 
stalses of the alimentary canal associated with pyloric stricture. 

4. A constriction of the pupil from central action, with dilation 
in the paralytic stage. 

III. 

Details of Pharmacological Action. 

i. The central nervous system. — The action of morphine on the 
central nervous system varies greatly. In animals there is a marked 
variation in response by the different species, especially among the 
mammals. In man the general picture is one of slight initial increase 
of function followed by very marked depression. 

The first and primary effect on man of a mild dose of morphine, 
and especially of opium, is a gradual diminution in the activity and 
control of the higher psychic centers. There is a marked decrease 
in the power of attention, followed by a dreamy, sleepy, imaginative 
state which is the condition desired by the opium abuser. This stage 
is characterized by lack of power of consecutive thought, a diminution 
of acuteness of judgment, and inability to long maintain effort if it 
involve logical sequence. The picture evidently indicates a selective 
action on the association centers and other higher psychic centers 
of the cerebral cortex. There is a certain degree of excitement some- 
times shown in the so-called imaginative stage somewhat similar to 
that produced by certain alcohols, especially absinthe. However, mor- 
phine is much more sedative and does not lead to the excessive mus- 
cular activities produced under the former drug. Morphine greatly 
reduces the power of self-control, therefore leaves the individual in 
the position of a reflex animal. 

In the incipient stages of morphine intoxication there is a delay 



ACTION ON THE NERVOUS SYSTEM 69 

in the facility with which intellectual acts are accomplished. This 
is quickly followed by a languid state in which the individual is 
aroused only by much more vigorous stimuli than are usually required. 
He may pass into a dreamy, sleepy state in which the sensations of pain 
are greatly blunted. The usual reflexes from stimulation of the 
skin are very greatly decreased though not eliminated. The change 




> Voluntary 
MovemtntUet 



Cannot Control 
movement 

\ Ga.nn.ot jump 
Unableto reeover 

pos ition when laid,, 
on t£s back. 



Pig. 14. — Dorsal view of the frog's brain. The legend shows the progressive 
effect of morphine and other narcotics which destroy the higher functions of the brain 
in the descending direction, i.e., in the reverse order of" their racial development. 
Dixon. 



depends upon the central depression rather than any direct effect 
upon the peripheral sensory apparatus. The chief value of morphine 
as a medicinal agent depends upon this characteristic reduction of the 
sensitiveness of the central nervous system to pain stimulation. In 
fact, morphine is probably the best known and most valuable alle- 
viator of pain in the whole category of drugs. 

With excessive doses of morphine the person lapses into a deep 
sleep from which he is awakened only with extreme difficulty, and 
even then only into a semi-conscious state. However, even in the 
advanced toxic stage, i.e., until respiratory paralysis is approaching, 
he can be aroused sufficiently to move around. Power of voluntary 
movement is only lost in the final toxic stage. In this deeply toxic 



70 



MORPHINE AND THE OPIUM SERIES 



condition the centers of the spinal cord have their irritability very 
sharply diminished, also the controlling medullary centers. The toxic 
action of the morphine falls very heavily upon the reflex mechanism 
within the cord without completely paralyzing it, hence this mechan- 
ism can be set into action, but only with the most profound cutaneous 
stimulation, a fact to be remembered in the treatment of morphine 
intoxication. 

The depression of the medullary centers falls most largely upon 
the respiratory center. The respiratory rate is greatly diminished 
according to Cushny 1 without suppressing the responses of the center 
to sensory stimulation and to the direct stimulation of carbon dioxide, 




0" 



20' 



40" 



100' 



120" 



140' 



160' 



180" 



Fig. 15. — The influences of C0 5 inhalations on the respiratory rate and amplitude 
before and after morphine. The tests of carbon dioxide were given 6 minutes before 
morphine, and 21 minutes after morphine. The rate and depth of respirations are 
represented by the ordinates. Time in 20 second intervals. Cushny. 

— — — depth before morphine. respiratory rate before morphine. 

depth after morphine. respiratory rate after morphine. 

though this latter response is greatly lessened in absolute amount. 
The amplitude is little decreased except in the very toxic degree of 
action. In the late stages of morphine intoxication the rhythm en- 
tirely ceases and death follows from the respiratory failure. 

2. Morphine on the circulatory system. — The responses of the 
circulatory system to morphine are complex, since the drug acts at 
several points in that system. Blood-pressure studies on mammals 
show, as a rule, a marked fall of pressure if morphine is injected 
intravenously in a relatively strong dose. The fall is accompanied 
by a large beat, but very slow heart rhythm, together with a peripheral 
vascular dilation. If the vagus nerves are severed the heart rhythm 
is more rapid, although a decided fall in the pressure still occurs. 

3. The reactions of the heart and its nervous mechanism. — The 
heart is affected by morphine in two ways, primarily by change in 

1 Cushny, A. R.: Jour. Pharm. and Exper. Therap., Vol. IV., p. 363, 1913. 



THE REACTIONS OF THE HEAKT 71 

the functional influence of the nervous complex, and secondarily 
through the direct action of the drug on the cardiac muscle. The 
heart rate is reduced to half or even less of its normal rate with a 
characteristic large and swinging amplitude, when a small to medium 
dose of morphine is given an otherwise undrugged animal. This 
effect comes from a primary and sharp stimulation of the inhibitory 
center in the medulla. If, in a mammal, the vagus nerves are sec- 
tioned before morphine is injected, the heart rate instead of slowing 
is markedly accelerated, a fact which may be interpreted as a direct 
stimulation of the accelerator center, see Figure 17. In this latter 
case there is still a great fall in the blood-pressure which is indicative 
of a general vascular dilation, an effect that can be explained by either 
of two conceptions, namely, vasodilator stimulation or vasocon- 
strictor paralysis. In light of the positive evidence as regards the 
cardiac centers one is inclined to consider the phenomenon a positive 
vasodilation. 

With the stronger intoxication from morphine these stimulative 
reactions on the medullary vascular centers pass into depression, i.e., 
narcosis. 

Morphine directly influences the rhythm, the contractility, and 
probably the conductivity of cardiac muscle. The rhythm is more 
profoundly depressed, though the amplitude may be, and generally is 
greatly diminished. Isolated portions of cardiac muscle, when bathed 
by relatively strong solutions of morphine may have the rhythm com- 
pletely obliterated. This influence is of the nature of a narcosis and 
can be slowly removed by eliminating the contact of the drug. Un- 
doubtedly this direct influence of morphine on heart muscle is a 
factor in the complex of the symptoms with all stronger doses of 
morphine, but does not appear in the reaction to therapeutic con- 
centrations. 

Recently Eyster and Meek x have shown that the intravenous and 
subcutaneous administration of morphine to dogs not only slows the 
heart, but produces characteristic irregularities in the cardiac action. 
Intravenous injections of 30 to 60 milligrams of morphine usually 
slightly increase the pulse for a few minutes, then there comes on 
a marked slowing of the rhythm. Still later there develops arrythmia 
in which there may be a sino-auricular block or an auriculo-ventric- 
ular block. " Electrocardiographic records indicate that the slowing 
and arrhythmia are due to disturbance of conduction between the 
point of origin of the cardiac impulse and the auricle, and between 
1 Eyster and Meek, Heart, Vol. IV., p. 62. 



72 



MORPHINE AND THE OPIUM SERIES 



the auricle and ventricle. ' ' At any time during the irregularity of 
the heart rhythm the administration of atropine completely recovers 
the regular rhythm. This antagonism of atropine for the morphine 
effect leads the authors to conclude that the peripheral cardiac change 
is a vagus effect. This view has been strengthened by the known 
fact that vagus stimulation may lead to similar blocks of cardiac 
conduction. 

EFFECT OF MORPHINE ON THE ELECTROCARDIOGRAM (EYSTER AND MEEK) 



Exp. 


Normal 


After Morphine 




P 


Q 


R 


s 


T 


RT 


P 


Q 


R 


s 


T 


RT 


6 


3 


6 


25 


6 


-7 


0.192 


1.5 


2 


19 


6 


+6 


0.227 


7 


3 


14 


27 





-5 


0.240 


2 


8 


28 





-1 


0.280 


8 


2 


9 


33 


6 


+2 


0.207 


1 


6 


30 


6 


+2 


235 


9 


3 


8 


30 


6 


-4 


0.185 


0.5 


6 


24 


5 


+3 


235 


10 


2 


6 


25 


6 


-2 


0.243 


1 


2 


19 


6 


+3 


0.262 



4. A review of the normal movements of the stomach and in- 
testine. — The stomach is divided into the two great cavities, the 




Fig. 16. — Intravenous injection of 2 cc. of 1 per cent, morphine on blood-pressure 
and respiration. Vagi intact, dog. The respiratory rates and heart rates as shown. 
Time in seconds. 

A, 10 seconds before morphine. D, after 4 1-2 minutes. 

B, 30 seconds after morphine. E, after 7 minutes. 

C, after 2 minutes. F, after 2S minutes. 



fundus and the pylorus. These cavities are bounded by muscular 
bands, the cardiac sphincter, between the esophagus and the stomach, 
and the pyloric sphincter at the boundary between the pylorus and 



MOVEMENTS OF THE STOMACH 



73 



duodenum. A cardiac-pylorus sphincter between the fundic and 
pyloric parts has been described but is questioned. The muscular 
walls consist of the general circular and longitudinal muscle coats, the 
special muscular sphincters being only thickened modifications of the 





RATE 13 



RATE 157 B 




RATE 10 



RATE 140 



Fig. 17. — The influence of morphine on blood-pressure and respiratory rate. Vagi 
cut. Experiment on same animal as Fig. 16. A, immediately after injection of mor- 
phine ; B, 1 1-2 minutes later ; C, 6 minutes later. Still later stages of this experiment 
show slow but gradual recovery similar to but not so rapid as in Fig. 16. 

The respiratory rates and heart rates as shown. 

circular muscle. "When the stomach is completely relaxed the sphinc- 
ters are passive, but when the stomach is filled as with food, then they 
are thrown into tonic contraction. Cannon has recently shown that 
the regulation of the contractions of the cardiac and of the pyloric 
sphincters is dependent upon an acid stimulation, the " acid 
closure." The acid of the gastric juice, largely secreted in the 





ot,.n ' 


<o<<9 


0<o*9 


bio 


tffevo 


Oh-io : 


O loUO \ 


701 


C 76V 


ObZi 




i_ 


oyzi 


0<o23 


1 Ob1Z 


I o fc33 


4.;j- 


I Ob23 


Olo.'iZ 


1 


i 38f 


1 06SV 1 


1 




^\oio* 




\o«i 




\««; 








\0 2.0 1 


1 1 1 9k9 



Fig. 18. — Diagram showing effects of morphine on heart conduction. Graphic 
Interpretation of an eloctrocardiogram. Eyster and Meek. 



fundus, stimulates a reflex mechanism which results in the contraction 
of the cardiac sphincter. In like manner, when discharge takes place 
of the acid content of the stomach into the upper end of the duodenum, 
the acid again stimulates a reflex nervous mechanism which results in 
the similar reflex contractions of the pyloric sphincter. In a few min- 



74 



MORPHINE AND THE OPIUM SERIES 



utes after food enters the stomach there is set up a series of regular 
peristaltic contraction waves, beginning at first in the zone intermediate 
between the cardiac and pyloric regions and progressing in orderly se- 
quence toward the pyloric end of the division. These waves originate 
successively nearer the cardiac orifice until they ultimately involve 
the whole stomach. The waves progress over the stomach at a re- 
markably uniform rate — in the cat, where Cannon first described 
them, one wave in ten seconds, requiring about twenty seconds for its 




Fig. 19. — Diagrammatic representation of the scheme of innervation of the ali- 
mentary canal. A, mucosa ; B, sensory nerve endings ; C, gastric or intestinal wall ; 
B and E, sensory and motor cell bodies in the enteric plexus ; M, motor neurons, 
vagus fibers for the stomach and upper portion of the intestine, sympathetic fiber 
lower down ; S and 8', afferent sensory nerves ; Sy, sympathetic ganglion, pre-postgangli- 
onic synapse, inhibitory path for the mammalian canal. The fiber 8' is introduced to 
Dixon's original figure on the basis of his foot-note. Modified from Dixon. 



completion. In man the waves continue during digestion or until 
the stomach is completely empty, six to eight and more hours. The 
peristalses control, therefore, two factors ; first, by their pressure over 
the food mass they produce a gentle kneading of the gastric juice 
into the food, and second, after the surface of the food is eroded off 
by the digestive process the waves of muscular contraction carry it 
forward toward the pylorus, which periodically relaxes, permitting 
discharge into the duodenum. Each discharge of acid food into the 
duodenum leads to a reflex closure of the muscular sphincter, hence 
the mechanism insures an even and regular feeding of the intestine 
from the great reservoir, the stomach. 



ACTION ON THE STOMACH 75 

\ 

Two sets of nerves control the muscular movements of the stomach ; 
first, the sympathetic nerves which reach the stomach by way of the 
splanchnics, and are inhibitory in character, and second, the vagus 
nerve, which is motor in character. The elaborate nerve plexuses of 
Auerbach and of Meissner form a local enteral nerve mechanism that 
is not yet fully understood. The indications are that the sympathetic 
nerve fibers run through these plexuses to end on the muscles, while 
the vagus fibers form synapses in these plexuses. That the stomach 
possesses sensory nerve endings can no longer be questioned (Pawlow). 
These endings are involved in the production of the secondary gastric 
secretions, through stimulation by the products of digestion which 
result in reflexes terminating in the gastric glands. There is some 
evidence that the sensory mechanism may produce local reflexes 
through local ganglia in the walls of the organ. 

The intestine also possesses circular and longitudinal muscle coats, 
but the only valve-like arrangement is that between the ilium and 
the colon, the cecal valve. The two types of muscular contraction 
occur, one a progressive peristalsis, which, under certain conditions, 
may become reversed, anti-peristaltic, and second, alternate contrac- 
tions and relaxations of adjacent portions of the circular musculature, 
described as segmentations by Cannon. The segmentations intimately 
mix and knead the intestinal content, while the peristaltic waves 
periodically drive the content along the tube. The nervous mechan- 
ism regulating the muscular movements is similar to that just de- 
scribed for the stomach, i.e., there are motor fibers, inhibitory fibers, 
and local ganglia. 

5. The action of morphine on the stomach and on the intes- 
tine. — It is obvious that the alimentary tract may be influenced by 
morphine through the action of the drug at any one of the following 
series of points : 

1. The motor centers in the medulla. 

2. The inhibitory centers in the medulla. 

3. The pre-ganglionic ends in the peripheral ganglia of the vagus 
path. 

4. The pre-ganglionic endings of the inhibitory path. 

5. The motor endings of the vagus post-ganglionic neuron. 

6. The inhibitory endings of the splanchnic ganglionic neuron. 

7. The muscle tissue directly. 

8. The local sensory apparatus. 

There is great variation in the effect of morphine on the alimen- 
tary tract of animals of different species. In man the initial effect 



76 



MORPHINE AND THE OPIUM SERIES 



is to produce a degree of nausea with the accompanying reflex increase 
in the secretions of the glands and sometimes vomiting. This nausea 
is not produced until absorption is accomplished and is undoubtedly 
through the agency of the vomiting centers of the medulla. In dogs 
and in the lower mammals vomiting almost invariably occurs, but in 
man only a mild degree of nausea is the rule. The nausea is limited 
to the earlier stages in morphine narcosis. It may reappear in the 
recovery stages following deep narcosis. That the nausea is not due 
to any peripheral action is indicated by the fact that it comes on 




Fig. 20. — Morphine 30 milligrams given subcutaneously to a cat. Rontgen-ray 
photographs of the stomach after a meal of potatoes, containing bismuth subnitrate. 1, 
normal stomach uniformly filled, showing pyloric peristalsis ; 2, 32 minutes after mor- 
phine, showing general contraction of the stomach wall, pyloric peristalsis ; 3, one hour 
after morphine, strong contractions of middle region of the stomach, pyloric peristalsis ; 

4, after 3 hours, fundus widely dilated, middle segment contracted, pyloric peristalsis ; 

5, after 6 hours, middle region of the stomach strongly contracted, separating the fundus 
from the pylorus. After Magnus. 



whether the drug be given by way of the mouth or by the hypodermic 
needle. 

The effect on the movements of the stomach is slight at first, usually 
producing in man only a mild increase in peristalsis. In dogs with 
duodenal fistula it has been observed that morphine greatly delays 
discharge of the content of the stomach. Magnus, using the Roentgen 
ray method of Cannon on cats and dogs, found that under the in- 
fluence of morphine the food remained stagnated in the fundic end 
of the stomach, due to cramp contractions of the cardiac-pyloric 
region. And although peristaltic waves traveled over the pyloric 



ACTION ON THE INTESTINE 77 

antrum, the pyloric valve, too, remained closed. Since this contrac- 
tion cramp persisted for several hours the discharge of the fundic 
content was markedly delayed, 7 to 24 hours, instead of occurring in 
the normal 3 hours. It is evident that morphine will produce the 
same general failure in emptying of the stomach as that occurring in 
various pathological conditions, such as atonia. Though the mechan- 
ism affected is different, a stagnation of the food takes place in each 
case together with fermentation and decomposition. How morphine 
brings on an increased contraction of the sphincters has not been 
adequately explained. One can but draw the inference that this 
effect is primarily central and is similar to that which produces an 
inhibition of the heart through the vagus mechanism. 

Morphine also influences the peristalses of the intestine. A rela- 
tively small dose increases peristalses, but the stronger doses tend 
to depress apparently by lowering the irritability and contractility of 
the muscle walls. These facts have been brought out by comparative 
studies on mammals. In some animals, especially the dog, the in- 
testinal contractions are sharply increased at the beginning of the 
influence of morphine. The dog exhibits, not only nausea and vomit- 
ing, but purging as well. Even in man, occasional individuals will 
be found showing this greater sensitiveness to morphine. These 
effects in the early stages of morphinization are undoubtedly due to 
central stimulation of the vagus-motor fibers for the intestine, and 
of the centers probably spinal, controlling the lower part of the 
alimentary canal, the colon and rectum. In the later stages, the 
symptoms are due to paralysis of the nerve endings. 

However, in man morphine and opium have long held a reputation 
for producing constipation. Magnus' work, previously quoted, gives 
one clew to the explanation of this effect on the intestine. Another 
factor has been cleared up by Pohl. Pohl studied the motor mechan- 
ism of the intestine after bilateral section of the splanchnics, i.e., the 
inhibitory paths. In normal animals this operation is accompanied by 
an increase in the sensitiveness of the responses of the canal to vagus 
stimulation, a sensitiveness that lasts several hours. If at any time 
after splanchnic section, morphine be given there is a marked decrease, 
in fact practical disappearance, of vagus control over the intestine. 
Notwithstanding this elimination of vagus endings there is an increase 
in peristaltic activity. This observation of Pohl, together with that 
of Magnus on the stomach, would seem to receive explanation in 
the action of the morphine on the local neuro-muscular mechanism. 
The exact point of action is somewhat a matter of inference, and one 



78 MORPHINE AND THE OPIUM SERIES 

is naturally influenced by his physiological conception of the origin 
of alimentary peristalses. 

6. Morphine on the eye. — Morphine produces a characteristic 
contraction of the pupil of the eye. Up to the extremely toxic stage 
the pupil is contracted down to a pin point, which is one of the 
diagnostic symptoms in morphine poisoning. The explanation of this 
action is also in dispute, since it might result either from paralysis 
of the dilator mechanism or from stimulation of the constrictor. The 





A. 



c. 

Fig. 21. — Action of morphine on the isolated loop of the small intestine, suspended 
in Ringer's solution. Rabhit. A, normal movement ; B, stimulating effect of 0.042 per 
cent, morphine hydronitrate ; C, paralyzing effect of 0.142 per cent, of morphine. From 
Magnus. 

constrictor mechanism is, indeed, the probable cause of the constric- 
tion, not by a stimulus of the center as one might suppose, but rather 
by a morphine narcosis of some central mechanism normally acting 
as an inhibitor of this center, thus setting free the normal tone of 
the center. That it is not local is proven by the non-effect of the 
drug in local applications. 

7. Morphine on the Frog. — The frog is a simple animal for 
the study of the effect of morphine, because of its lesser complication 
of nerve structure. The simple brain of the frog can be removed 
part by part, and the physiological effects of such removal are 
well known. Morphine given to the frog diminishes the ac- 
tivities of the animal, suspending the functions of the brain in a 
descending series in a way closely comparable to the type of change 
noted when the parts of the brain are removed by operation. After 
a toxic dose for a frog has been acting for several hours, from six to 
twenty-four, the spinal cord begins to show a marked increase in 
sensitiveness to reflex stimulation. A slight stimulus may lead to 
regular muscular spasms not unlike those produced by strychnine. 
In the ordinary acute effect of the drug this stage is not observed on 



CODEINE, PAPAVERINE, THEBAINE, HEROIN 79 

the frog, but in the cat it is often approached early, due to the 
extraordinary sensitiveness of the cord and brain-stem of this animal 
to morphine. Interest in this strychnine-like effect is brought out 
by a comparison with other members of the morphine series. These 
produce increasing stimulation in the order in which the drugs are 
named on page 66. Thebaine, for example, produces a change in the 
central nervous system closely comparable to strychnine itself. In 
the cat morphine produces a thebaine-like type of poisoning. 

8. Morphine on metabolism. — Morphine decreases metabolism. 
This is shown by measuring the amount of nitrogen eliminated during 
morphinization. Various observers have shown that the total amount 
of nitrogen eliminated during morphine narcosis is very markedly 
diminished. Along with the decreased metabolism is generally noted 
a decrease in body temperature. The fall of blood-pressure and 
dilation of the cutaneous blood-vessels lead to a greater heat loss. 
This, without the necessary increase in heat production, a normal 
response to lowered temperature that is reduced if not suppressed 
under morphine, leads to a fall in the average body temperature. 

Morphine produces some specific changes in the body metabolism, 
as for example, in the glycogenic function of the liver. Under its 
influence the sugars are eliminated from the body in greater quantity, 
for a certain degree of glycosuria generally follows the giving of 
morphine clinically. 

IV. 

Action of Codeine, Papaverine, Thebaine, and Heroin. 

The alkaloid, codeine, produces effects similar to morphine. The 
chief difference is in the relative increase in the various stimulative 
phases and a decrease in the depressions noted under morphine. 
Codeine produces a distinct narcosis, but the sleep is not so pro- 
nounced as that produced by morphine. A greater degree of excita- 
tion follows the use of larger doses. It is also claimed that codeine 
more markedly stimulates the vascular nervous mechanism, leading 
to a greater fall of blood-pressure with greater dilation of peripheral 
blood-vessels than occurs with morphine. 

Codeine does not produce so great a depression of the respiratory 
center and is therefore to be preferred to morphine, especially with 
children. Codeine is only about one-twentieth as toxic as morphine, 
a variation that rests largely on its decrease in toxic influence over 
the respiratory center. 



80 MORPHINE AND THE OPIUM SERIES 

Papaverine has a narcotic influence very similar to that of codeine. 

Narcotine has a more specific influence on the spinal cord and 
its action resembles thebaine, though it is not so toxic. 

Thebaine, in comparison with the other members of the morphine 
series, possesses far less narcotic and more stimulating powers. The- 
baine on animals often produces mild muscular spasms very similar in 
character to those following a mild dose of strychnine. In the cold- 
blooded animals, frogs and turtles, this strychnine-like action is an 
early symptom, while the similar action of morphine comes on only 
after many hours and following a deep narcotic stage. Reference 
to the chemical formula shows that thebaine contains two methyl 
groups in substitution for hydrogens of the two hydroxyls in the 
morphine. This substitution is undoubtedly the cause of the dimin- 
ished narcotic and the increased stimulating effect of the thebaine. 

Heroin. Of the synthetic or artificial alkaloids derived from 
members of the morphine group, heroin may be especially mentioned. 



/0-CH 5 
CH 3 CO.O. / | 

^C^Hiox CHj 



CH 3 CO.o/ 

Heroin 



N.CHs 



The two acetyl substitutions produce in heroin a desirable sedative, 
acting mildly on the respiratory apparatus and on the pain mechan- 
isms. Heroin is not considered so toxic as morphine. 



The Excretion of the Morphine Group. 

Morphine is partly oxidized, but also excreted from the body un- 
changed. A hypodermic injection of morphine is eliminated by ex- 
cretion through the glands of the alimentary tract, and the mucous 
membrane of the stomach and intestine. Faust x shows that 70 per 
cent, can be recovered from the feces of a non-immunized animal. 
A certain proportion of the morphine is temporarily combined by the 
tissue protoplasm, but this is gradually set free and is usually ex- 
creted in from two to three days, Cloetta, 1903. The excretion be- 
gins at once and can be detected both in the saliva and in the secre- 

1 Faust, Edwin S. : Archiv f. Pathologie und Pharmakologie, Bd. 44, S. 217- 
238, 1900. 



THE ABUSE OF OPIUM 81 

tions of the stomach within a few minutes after its injection. In 
dogs even the vomit produced shortly after hypodermic injections, and 
as a result of morphine, has been shown to contain excreted morphine. 
A trace of morphine is excreted by way of the kidney. 

With continuous use of morphine the oxidizing power of the tis- 
sues increases, thus leading to a degree of tolerance which is very 
marked. A chronic opium user will consume enough morphine at a 
single dose to kill one unaccustomed to the drug. Faust tested the 
basis for this tolerance. He gradually increased the daily hypo- 
dermic dose of morphine hydrochlorate given a 6.7 kilo dog. The 
initial daily dose was 0.045 grams. After ten weeks the animal re- 
ceived daily 2.5 grams, all of which was oxidized. On the 86th day 
3.5 grams produced only a general " soporific " condition. A dose 
of 1.5 grams of morphine is toxic to a normal dog of the weight of 
the one used by Faust. Faust expresses the belief that the' apparent 
tolerance is in reality ability to oxidize, and that the tissues do not 
become non-responsive to the alkaloid. 

Codeine is also excreted in large per cent, unchanged, in this case 
also through the feces, but to a larger extent through the urine. 
Tolerance is not acquired for codeine to the same degree as for 
morphine. 

VI. 

The Abuse of Opium. 

Opium has been used for ages as a means of producing physio- 
logical and psychological states considered more or less desirable by 
the victim. Opium is used for smoking, in snuffs, and for eating. 
A favorite means of using morphine is by hypodermic injections. 
The chronic user is striving for the mental effects that characterize 
the earlier stages of morphine action. 

The Oriental peoples are the chief abusers of the members of 
this series, especially in the East Indies and in China. In fact the 
use of opium in China was forced as a commercial proposition and 
stands to the discredit of the English people. At the present time, 
in the United States, there is a considerable use of opium for smoking, 
and of morphine taken by the method of hypodermic injection. 

The smoking of opium is a favorite method among the " opium 
victims." It produces a mental state or intoxication in which 
the individual experiences an elation characterized by dreamy yet 
vivid imaginings. The individual use of the drug would not be 



82 MORPHINE AND THE OPIUM SERIES 

so deplorable except for the fact that there is a marked tendency 
for habit formation, from which it is next to impossible to escape. 
The tissues of the body acquire increased oxidizing power and a toler- 
ance for the drug, and along with this an irresistible demand for it. 
The victim has no power of resistance. He not only requires the drug, 
but will obtain it at the sacrifice of all the moral and intellectual 
restraints which modern society ordinarily holds inviolable. 

The effect of chronic opiumism on normal metabolism is very great. 
Morphine interferes with the usual oxidation processes. This de- 
presses growth and development, leads to degeneration and weakness, 
in short, contributes to the general bodily degradation. Under this 
condition the body is in a real pathological state, therefore morphin- 
ism must be looked upon from the standpoint of disease. The tissues 
in such condition reach a state in which the total deprivation of 
morphine becomes intolerable to the victim. The only way to relieve 
him is by the gradual reduction in the amount of morphine, asso- 
ciated with the best of conditions favorable to normal nutrition. 
In practice this has been found to be possible only in special sana- 
toria where the physiological needs of the individual are supplied, 
and at the same time he is put under restraint that yields the control 
of practical imprisonment. 



VII. 

Condensed Summary of the Action of Morphine and the Opium 

Series. 

Morphine is a narcotic and sedative, acting primarily on the 
central nervous system. It produces a mild but brief stimulation, 
followed by a decrease in function of the cerebral cortex, beginning 
with the higher psychic centers and acting in a descending direction. 
In the nerve centers of the medulla the most profoundly influenced 
is the respiratory center, which, after a brief acceleration, diminishes 
in sensitiveness and is ultimately paralyzed by toxic doses. The spinal 
cord is decreased in its sensitiveness to reflex stimulation, but in the 
late toxic stages, especially in the lower animals, often shows a 
decreased resistance, bordering on the convulsive. The circulatory 
system is markedly depressed in its efficiency. Blood-pressure falls, 
due in the early stages to slowing of the heart through the action of 
the inhibitory center and to peripheral vasodilation, but in the later 
stages to direct depression of the cardiac rhythm and to vasodilation 



SUMMARY OF ACTION OF MORPHINE AND OPIUM 83 

through loss of vasomotor control. The pupil is constricted, but this 
passes into dilation with the final toxic stage. 

Morphine produces nausea and vomiting chiefly through central 
action on the vomiting center. It produces an initial increase in the 
peristalsis of the alimentary tract, followed by marked depression of 
alimentary efficiency because of contraction spasms of the pyloric 
stomach. The initial stimulation is slight in man, but very marked 
in certain mammals where morphine often leads to marked purging 
as well as vomiting. The depressing effect on peristalsis is due to 
depression of the extrinsic nerves controlling the alimentary tract, 
coupled with stimulation of the local mechanism. Morphine lowers 
metabolism, diminishing the excretion of nitrogen. It also influences 
special metabolisms, such as the glycogenic function of the liver. 
Morphine is excreted chiefly through the alimentary canal, 70 per 
cent. A trace is eliminated by the kidney and there is some oxidation 
by the tissues. Oxidation increases with prolonged use, and tolerance 
is acquired for morphine largely through increased oxidative powers 
and the adaptation of the tissues to its presence. In extreme toler- 
ance the daily quantity used may reach ten times an ordinary toxic 
dose. Other members of the morphine series, in the order of increas- 
ing methyl substitution, as in codeine and thebaine, produce similar, 
though less intense narcotic effects, but with greater stimulation. In 
thebaine the stimulative action, especially on the spinal cord, ap- 
proaches the convulsive. 



CHAPTER VIII. 

APOMORPHINE AND APOCODEINE. 

I. 

Historical and Chemical. 

Certain drugs produce emetic effects so definitely and character- 
istically that they have come to be used in therapeutics for that 
action alone. Of these, one of the best known and characteristic is 
apomorphine. Apomorphine is derived from morphine by dehydra- 
tion which can be accomplished by various dehydration agencies 
such as acid, etc., according to the formula: 

C H NO —H = C H NO . 

17 19 3 2 17 17 2 

Morphine Apomorphine 

In this chemical treatment the characteristic morphine actions are 
largely lost and there is a strong stimulating action developed in 
regard to special mechanisms in the central nervous system. 

Apocodeine is derived from codeine by similar treatment, which 
produces a loss of water from the molecule. 

II. 

Outline of Pharmacological Action. 

1. Apomorphine produces a strong stimulation of the vomiting 
center in the medulla which is specific. 

2. Stimulation of secretory centers for saliva, perspiration, etc. 

3. Paralytic action on skeletal muscle. 

4. Marked depression of cardiac muscle. 

5. Apocodeine is strongly paralyzing to the nerve paths in periph- 
eral ganglia, poisoning at the same point as nicotine. 

6. Apocodeine is toxic to all forms of motor nerve endings. 

III. 

Details of Pharmacological Action. 

Morphine itself has a twofold action which, in its discussion, has 
been described in some detail, namely, a stimulating action, and a 

84 



ACTION ON THE NERVOUS SYSTEM 85 

depressant action. In its transformation into apomorphine the alka- 
loid has lost practically all of its latter pharmacological properties, 
but has retained the property of stimulating, especially for certain 
portions of the nervous tissue. 

i. On the central nervous system. — Apomorphine acts chiefly 
stimulative to the medullary centers controlling the glands and the 
alimentary canal. This action is specific on the vomiting center. A 
hypodermic injection of eight to ten milligrams will produce nausea 
and vomiting in man in ten to twelve minutes. After vomiting the 
symptoms ordinarily rapidly disappear. The premonitory changes 
are a feeling of weakness, increase in the secretion of saliva and of per- 
spiration, and a feeling of warmth over the skin. With larger doses 
there may be repeated vomitings followed by languor and a certain 
degree of collapse. The dangers from apomorphine are relatively 
slight, depending largely on a tendency to paralysis of the motor 
centers. 

Other nerve centers in the medulla are sharply stimulated by 
apomorphine. For example, experiments on mammals show that the 
respiratory center is also accelerated and that an animal will breathe 
a relatively greater volume of air in a unit of time under the influ- 
ence of this drug. This is in marked contrast to the action of mor- 
phine, which produces the opposite effect on the respiratory volume, 
notwithstanding the incipient respiratory acceleration. All those 
glandular mechanisms under the control of the nervous system, such 
as the salivary and buccal glands, the glands of the respiratory tract, 
the sweat glands, the lachrymal glands, etc., are set into vigorous 
secretion. Apomorphine is therefore an active expectorant and 
diaphoretic. There is some evidence of increased spinal sensibility, 
which shows itself in the accelerated general activity of such animals 
as the cat. However, the excitation which this animal shows, quite 
characteristic under morphine also, may be explained on the assump- 
tion of some degree of hyperirritability of its nervous mechanisms, 
i.e., of the higher centers. 

In animals which do not have well developed the ability to vomit, 
the stimulating action of apomorphine is readily demonstrated by 
its action on other portions of the central nervous system. Such 
animals become restless and more active, but their movements are 
uncoordinated. The cat, for example, shows an increased motor ac- 
tivity quite comparable to its behavior under morphine itself. In the 
late stages, following strong doses, nervous paralysis sets in, the reflexes 
are lost and death may follow from respiratory failure. 



86 



APOMOKPHINE AND APOCODEINE 



All the symptoms associated with apomorphine emesis are readily 
explained on the assumption of marked stimulation of the vomiting 
mechanism. This mechanism can be set into action physiologically 
by increasing the irritability of the sensory cells in the peripheral 
region, as for example in the mucous membrane in the stomach, or 
by direct action on the nerve cells in the vomiting center of the 
medulla. Violent irritation of the stomach mucosa, as for example 
by such irritants as mustard, strong salines, tartar emetic, etc., all 
result in the reflex production of vomiting. In the case of apomor- 
phine, however, vomiting results as readily when the drug is given 
hypodermically as when given internally. Eggleston and Hatcher 1 
have recently made a re-study of the question under the title, " The 
seat of the emetic action of apomorphine." By a guarded series of 
experiments they come to the conclusion " that all of the evidence 
favors the view that apomorphine acts directly upon such central 
mechanism, " i.e., the central controlling vomiting mechanism. 
Further, " that apomorphine acts solely by direct stimulation of the 
central vomiting mechanism in the dog and probably also in man." 
From their published experiments the following table of the effective 
apomorphine dose for the dog is compiled: 

Apomorphine dose for the dog (Eggleston and Hatcher). 



Method of Giving Apomorphine 


Milligrams 
per kilo 


Time before Emesis 


Stomach 


5.7 
0.2 

0.075 
0.045 


8 minutes 

7% minutes average 

4 minutes 













2. The depressant action on muscular tissue. — Apomorphine de- 
presses the irritability of skeletal muscle, as can readily be shown on 
the muscles of the frog. This effect is of significance on man, only 
where extremely toxic doses may have been given, since respiratory 
failure may be contributed to by the muscular paralysis. 

The heart is weakened from direct and toxic depression of the 
cardiac muscle. 

1 Eggleston and Hatcher: Journal of Pharmacology and Experimental Thera- 
peutics, Vol. III., p. 551. 



APOCODEINE 87 

IV. 
Apocodeine. 

i. The action of apocodeine on nervous structures. — Dixon * 
has published an exhaustive study of the pharmacology of apocodeine. 
He shows that all the numerous systemic effects which are observed 
after the display of this drug can be explained as due directly or 
indirectly to the toxic action on nervous tissue. For example, the 
injection of apocodeine, 1 to 2 mgr. per kilo, for a dog, leads to 
a marked fall of blood-pressure to a relatively low level, associated 
with a more rapid heart rate, and accompanied by evidence of vascular 
dilation in the periphery. If nicotine has previously been used, then 
these effects do not follow apocodeine. Also with the latter drug there 
is no initial rise of blood-pressure indicative of vascular stimulation 
as with nicotine. At the same time drugs which influence the periph- 
eral nerve endings, like epinephrine, continue to be active. It is 
obvious that the circulatory changes can be explained on the assump- 
tion that the nerve cells of the ganglia on the course of the autonomic 
fibers have lost their function, have been poisoned. 

After somewhat stronger doses of apocodeine the post-ganglionic 
fibers of the various autonomic paths are no longer functional. 
Stimulation of the accelerator nerves of the heart or of the splanch- 
nics does not give rise to cardiac acceleration or to visceral vaso- 
constriction. Yet drugs, like digitalis and barium chloride, which in- 
fluence the peripheral tissues, are still active (Dixon). All these 
observations indicate that the toxic influence of apocodeine is general 
for motor nerve endings. However there is a degree of selective 
action in that visceromotor and cardiac inhibitory nerves are para- 
lyzed by the weaker doses, the voluntary motor and the accelerator 
nerves of the heart by medium doses, and vasomotor by toxic doses 
of the alkaloid. For the cat 60 to 70 mgrs., given intravenously, elimi- 
nates the function of the cardiac ganglia, 100 to 120 mgrs. the vagus 
endings, and 250 to 300 mgrs. the cardiac accelerator nerve endings. 

2. On the alimentary canal and urinary motor system. — The 
paralysis of the nervous mechanism of the alimentary canal and of 
the urino-genital system leaves the motor structures of those systems 
free to give out their normal automatic contractions. The result is 
that the stomach, intestine, and urinary bladder are all thrown into 
increased muscular movements. This reaction led Dixon to suggest 
the use of apocodeine for the purpose of increasing smooth muscle 
'Dixon, W. E.: Journal of Physiology, Vol. XXX., p. 97, 1903. 



88 APORMORPHINE AND APOCODEINE 

contractions in cases of motor stagnation from over-inhibitory nerve 
stimulation. 

3. Apocodeine in support of pharmacological investigation. 
— After all, at the present time, with apocodeine as with nicotine, the 
value of the drug has been most striking in relation to scientific re- 
search. Rational medicine undertakes to demonstrate the exact re- 
actions in the body produced by medicinal agencies. The extraordi- 
nary complexity of the animal body has proven baffling in relation 
to the study of changes effected by many of the drug agencies. The 
discovery of a drug, which can definitely throw out of function the 
peripheral nerve endings of the autonomic system makes it possible 
to reinvestigate those drugs the action of which have been problem- 
atical, as for example pilocarpine, epinephrine, digitalis, etc. 

V. 

The Action of the Irritant Emetics. 

Emesis can also be produced reflexly by other substances. In this 
case any sufficiently irritant substance in contact with the gastric 
mucosa leads to a violent gastric irritation along with the excessive 
development of sensory stimuli. The effect of these stimuli, when of 
physiological intensity, is favorable in the stimulation of the nerve 
centers controlling the glands which pour their secretion into the 
alimentary canal, and which to some degree favor the development 
of alimentary peristalsis. When the stimuli become excessive all 
the medullary centers, including the vomiting center, are over- 
stimulated. 

Try Fig 74, Dixon, u. 275. 

Of these peripheral acting emetics there is a large series, but the 
following may be mentioned as the most important : 

Warm water, ' Mustard, 

Strong sodium chloride solution. Tartar emetic, 

Ipecac, Zinc sulphate, etc. 



B. General Stimulating Series. 

CHAPTER IX. 

THE CAFFEINE GROUP. 

I. 

Historical and Chemical. 

Caffeine and its relatives are vegetable alkaloids which are chemi- 
cally related to the purine-xanthine products of the animal body. The 
most widely used and best known of this group are caffeine, derived 
from the coffee berry, Coffea Arabica, and from the leaves of the tea 
plant, Thea Chinensis; and theobromine, derived from the seeds of 
Theobroma Cacao, which is a tree native to Central and South 
America. Tea leaves contain also theophylline. Several other plants 
contain small quantities of these alkaloids, of which may be men- 
tioned the cola nut of Africa, Cola acummata, which contains caffeine 
and theobromine. 

The chemical relationships of these alkaloids to the purine 
bodies is shown in the accompanying structural formula? of xanthine 
(dioxy purine), theophylline (1.3. dimethylxanthine), theobromine 
3.7. dimethylxanthine), and caffeine (1.3.7. trimethylxanthine). 



N= 

I 
HC 



X 



=CH 

I 

CN- 



■('- 



Purine 



-NH 



/ 



CH 



HN- 

I 
OC 



HN- 



-CO 

I 

C NH 



/ 



CH 



■H 



Xanthine — 2.G dioxypurine 



CH S N CO 

I I 
OC C NH 



CH 3 N 



-('- 



/ 



CH 



■N 



Theophylline— 1.3. dimethylxanthine 



CH 3 N CO 

I I 
OC C N.CIIs 



CH 3 .N 



89 



/ 



CH 



Caffeine— 1.3.7. trimethylxan thine 



THE CAFFEINE GROUP 



HN- 

oh 



-CO 

I 

c- 



-N.CH3 

> 

-N 



CH 3 N 

Theobromine— 3.7. dimethylxanthine 



HN 
OO 



HN- 



CO 

I 

c— 



-NH 



>co 



NH 



Uric acid 



II. 

Outline of Pharmacological Effects. 

Caffeine is one of the purest stimulating agencies acting on 
physiological mechanisms which has thus far been described. Its 
primary effects are: — 

1. The excitability of the central nervous system is increased 
in the descending direction, stimulation primarily of the cerebral 
cortex and later the centers of the spinal cord and the medulla. 

2. It increases the power of muscular contraction of all kinds of 
muscle. 

3. It is a cardiac and vasomotor stimulant. 

4. Caffeine is a vigorous diuretic. 



III. 

Details of Pharmacological Effects. 

1. Caffeine on the central nervous system. — The alkaloids of 
the caffeine group increase the irritability, and therefore the volume 
of the reactions, through the central nervous system at all points. 
Its stimulating effect falls, first and primarily, upon the cerebral 
cortex, especially on the higher psychic functions of the association 
centers of the cortex. It increases the delicacy of sensory perception 
by increasing the sensitiveness of the mechanisms of the cortex. As 
a result a given sensory stimulus produces a greater volume of 
psychic reaction during caffeine than before the use of this drug. 
The association of ideas is facilitated^ As a net result, the ability to 
do mental work and the volume of work done are both increased. 
It is evident that caffeine produces a change in the nervous complex, 
which facilitates the passage of nerve impulses, hence there is a 
tendency to alertness and fatigue is displaced by a feeling of com- 
fort. But, while caffeine is favorable to the greater production of 
psychic activity under stress, attention must be called to the fact that 
such a nervous whip is not without its exhausting after effects. 



ACTION ON THE SPINAL CORD 91 

The amount of physical work which a man can do depends, not 
only upon his muscles, but upon the neuro-muscular mechanism as a 
whole. Caffeine by its influence upon the nervous side of the machine 
alone, greatly increases the amount of physical work and endurance. 
Thus, in modern army regulations the well-known beneficial effects 
of caffeine are recognized by the addition of coffee to the ration dur- 
ing the execution of forced marches. A part of this influence of 
caffeine falls upon the muscular tissue, as will be explained later, 
but the main effect is in the stimulation of the central nervous system. 

With larger and especially with excessive doses of caffeine, ex- 
treme restlessness and nervous excitability occur and severe headache 
develops. In extreme cases there is some confusion of thought with 
a tendency in the toxic intensity of action to delirium and convul- 
sions. Many individuals are hypersensitive to caffeine and cannot 
endure the larger doses to which the average person gives only a 
moderate response. 

2. The spinal cord. — Caffeine and other members of the group 
add to the sensitiveness of the spinal cord. Reflex excitability is in- 
creased, though not to anything like the extent produced by strych- 
nine. Even the lower vertebrates show a greater response to cutaneous 
stimulations, in some cases approaching tetanus. These effects are 
shown more delicately on toads, Bufo, than on the usual laboratory 
frog, Rana esculenta, partly due to the characteristic motor activities 
of the former. 

3. The medulla. — Caffeine stimulates the nerve centers of the 
medulla, especially the cardiac inhibitory and the respiratory centers. 
In the case of the respiratory center the alkaloid apparently acts 
directly on the nerve cells, greatly increasing their sensitiveness. 
Respiratory stimuli, therefore, produce markedly greater discharges 
of motor nerve impulses. The respiratory rhythm is also sharply 
accelerated. 

4. The action of caffeine on the skeletal muscle. — Caffeine in- 
creases the amount of muscular work which can be voluntarily accom- 
plished, as shown by ergographic records. A percentage of this bene- 
ficial effect is due to central nervous action as previously mentioned, 
but apparently the larger part is due to the influence of the series 
on the muscular tissue. The most striking demonstration of this 
point is had from parallel records from the work of two gastrocnemii. 
If one muscle be allowed to absorb caffeine through the normal cir- 
culation while the other is kept free from the drug, and if parallel 
records be taken of the contractions in response to repeated stimuli 



92 



THE CAFFEINE GROUP 



of the same intensity applied to each muscle, it will be found that 
the drugged muscle will do from ten to thirty per cent, more work 
than the normal muscle. Skeletal muscle is also rendered more sensi- 
tive to stimuli so that the minimal stimulus has a smaller intensity 
in a caffeinized muscle. Larger, i.e., toxic, doses produce a persistent 
contraction and rigor, a fact that is of diagnostic value in dis- 
tinguishing between caffeine and strychnine in physiological toxi- 




Fig. 22. — The influence of caffeine 0.1 per cent, in blood-Ringers solution on the 
contractions of the isolated heart of a cat perfused through the coronary, arteries. The 
irregularity which appears in the last portion of the tracing continued to increase, 
showing periodical groups of extremely rapid rhythm. The regular rhythm was soon 
re-established. On repeating the experiment the rhythm was enormously increased and 
accompanied by even a more marked increase in amplitude. Time in seconds. New 
tracing by Boutwell, Miller, and Peeler. 



cology. This rigor can be produced by the different members of the 
series, including xanthine itself. 

Smooth muscle and cardiac muscle are similarly influenced by 
caffeine. 

5. Caffeine on the circulation. — The effect of caffeine on the 
general circulation is to produce a rise of blood-pressure. The 
degree of change is influenced by the somewhat antagonistic physio- 
logical effects of the stimulation of different parts of the circulatory 
mechanism. Therapeutic doses of caffeine produce a favorable rise, 
while the strong doses are apt to be followed by irregular results. 
This is explained by the details which follow. 



CAFFEINE ON THE VASOMOTOR APPARATUS 93 

6. Caffeine on the cardiac mechanism. — Caffeine and the other 
members of the series stimulate both the nervous mechanisms con- 
trolling the heart and the cardiac muscle, as shown in heart strips 
and in the isolated mammalian heart. There is an increase in the 
rhythm and a stronger contraction. This increases the discharge 
of blood from the ventricles, both from the increased volume of a 
single beat and from the increased number of beats for a unit of 
time. Undoubtedly this favorable influence on the function of the 
heart is due to direct action on the muscular tissue. This is proven 
by the influence of caffeine on isolated ventricular muscle from the 
lower animals. 

Xanthine, which is a product liberated in the mammalian body, 
also markedly stimulates the mammalian heart as shown by Kobert. 

Strips of terrapin's ventricle produce stronger contractions, and 
usually an acceleration of rhythm when bathed in graded strengths 
of solutions of caffeine. This favorable activity on the heart muscle is 
also shown in the perfused isolated frog's heart preparations where 
the amplitude is markedly increased and the rate slightly accelerated. 
In the frog's heart there is a tendency to systolic contracture, espe- 
cially in the late stages of the after effects. Cushny has demonstrated 
the favorable action of caffeine on the heart by direct records from 
the heart of mammals in situ. Caffeine produces both acceleration 
and increased amplitude under these conditions. 

The heart rhythm is often slowed by therapeutic doses of caffeine. 
This apparently contradictory action is due to a preponderant stimu- 
lation of the vagus center in the medulla. In the therapeutic dose 
the medullary stimulus is greater than the direct cardiac, hence there 
is relative slowing. By laboratory experiments it can be shown that 
minimal inhibitory stimuli for the vagus become subminimal after 
the injection of caffeine, which is due to the greater activity of the 
cardiac muscle and not to depression of nerve function. 

7. Caffeine on the vasomotor apparatus. — The vasomotor ap- 
paratus is stimulated by caffeine both centrally and peripherally. 
The vasoconstrictor center is set into greater tonic activity, which 
leads to increased peripheral constriction. The drug also produces 
a greater irritability of the smooth muscle, which adds to the periph- 
eral constriction of the arterioles. Hence there is a marked increase 
in the vascular resistance with a corresponding rise of blood-pressure. 
With excessive doses this peripheral constriction amounts to a vascu- 
lar spasm, and may thus influence the reactions of the tissues in 
secondary ways. 



94 THE CAFFEINE GROUP 

8. The action of caffeine on the respiratory mechanism. — The 
acceleration of the discharge of nerve impulses from the respiratory 
center under the influence of the caffeine series was mentioned while 
discussing the medulla. But the favorable reaction is in part due 
to the peripheral influence on the respiratory muscles. In all marked 
depressions of the respiratory mechanism, as from alcohol or in mor- 
phine narcosis, caffeine forms a splendid antagonistic drug. Con- 
siderable quantities of caffeine may be administered in such cases 
without running the risk of collapse in the after stages, of the kind 
which characterizes the effects of over-stimulation from strychnine. 

9. Caffeine on metabolism. — The study of the central nervous 
system, of the musculature, and the great circulatory and respiratory 
mechanisms, all indicate greatly increased functional activity under 
the influence of caffeine. It is obvious that metabolism in these 
special tissues is accelerated thereby. The metabolic increase is 
further indicated by the greater output of carbon dioxide and of 
nitrogen, and also by the rise in general body temperature. 

10. The diuretic action of caffeine. — Therapeutic quantities of 
caffeine, and especially of theobromine, produce marked diuresis in 
man and the mammals. The diuretic action may increase the output 
of urine per unit of time several hundred per cent., as demonstrated 
by Cushny on the rabbit. In man this increase may amount to 
fifty per cent, or more. Associated with the greater water output, 
there is an increase in the solids of the urine, both inorganic and 
organic. 

Considerable discussion has arisen as to how the favorable influ- 
ence of caffeine is accomplished. By some it is held that the diuretio 
action is secondary to the favorable action on the circulation. This, 
however, will scarcely account for the greater volume of urine some- 
times observed in low blood-pressure. It is more probable that the 
caffeine members act to increase the irritability of the renal epithelium 
in a way not unlike their action on muscular and nervous tissue. 
With toxic doses of caffeine there is occasionally complete suppres- 
sion of the urine, a result that is explained by the production of 
arterial spasms with shutting off of an adequate renal blood flow. 

11. The absorption and excretion of caffeine. — The alkaloids of 
the caffeine series are readily absorbed from the alimentary tract. 
They are excreted by the kidney, but only in small part unchanged. 
The greater part of the caffeine undergoes oxidation in the body, with 
loss of methyl, being converted into dimethyl or into monomethyl- 



SUMMARY OF ACTIOX OF THE CAFFEINE GROUP 95 

xanthine. The xanthine of caffeine origin is undoubtedly further 
oxidized in the body in the same way as the xanthine of animal origin. 

IV. 

Condensed Summary of the Action of the Caffeine Group. 

Caffeine is a primary nerve stimulant. Its action is char- 
acterized by descending stimulation, falling first upon the cerebral 
cortex and later upon the centers of the medulla and spinal 
cord. It produces a primary acceleration of psychic activity, 
a greater sensitiveness to the inflow of stimulation, which arouses, or 
at least supports, intellectual work. Caffeine also stimulates the 
motor nervous mechanisms of the spinal cord and the medulla. 
It increases the power of the skeletal muscle to do muscular work. 
Therefore it has a favorable influence over conditions of fatigue and 
exhaustion, coupled with a minimum of deleterious after effects. 
Respiratory activity is markedly accelerated, due to increased sensi- 
tiveness of the respiratory center and in part to an increase in the 
irritability of respiratory muscles. The circulation is favorably 
augmented by a rise of blood-pressure, and a slightly slower but 
stronger heartbeat. Heart muscle itself is rendered more irritable and 
its contractions more vigorous, but in therapeutic doses of caffeine, 
the stimulation of the inhibitory center overcomes the muscular ac- 
celeration. The arterioles are constricted, partly from direct mus- 
cular action and partly from increase in the tone of the vasomotor 
center. Metabolism in general is favored and the body temperature 
increased. Diuresis is produced by caffeine through primary stimu- 
lation of the renal epithelium. Anuria may result from an over- 
stimulation by the production of stricture of the arterioles. Caffeine 
loses its methyl and is oxidized down to monomethyl xanthine and 
uric acid in which forms it is largely excreted. A portion may be 
excreted unchanged. 



CHAPTER X. 
THE STRYCHNINE GROUP. 

I. 

Chemical and Historical. 

Strychnine is an extremely toxic alkaloid, found together with its 
relative brucine in the various species of Strychnos. These alkaloids 
are present in the largest quantity in the seeds, but are also found 
in portions of the bark and wood. The best known species from 
which the alkaloids are obtained are Strychnos nux vomica, and 
Strychnos ignatia. The seeds of Ignatia contain about two per cent, 
total alkaloid, three parts strychnine, and one part brucine, of nux 
vomica from 2.6 to 3.9 per cent, of the two alkaloids, about equally 
distributed. Strychnine is much more toxic than brucine, in about 
the ratio of 1 to 50. The chemical formulae of the two alkaloids are : 

C21H22N2O2 = C20H22O — CO 



Strychnine 



r 



C 23 H 26 N 2 04 = C2 H2o(OCH 3 ) 2 0— CO 

M 

Brucine 

The brucine differs from strychnine in that it contains two oxy- 
methyl groups. Both alkaloids are very insoluble in cold water, but 
they readily form salts, which are soluble. 

II. 

Outline of Pharmacological Action. 

1. Strychnine increases the irritability of the spinal cord and 
the central nervous system. 

2. It causes convulsions and tetanus in toxic doses. 

96 



DETAILS OF PHARMACOLOGICAL ACTION 97 

3. It increases the sensibility of special sense organs. 

4. Tonic reflexes are produced by the bitter taste. 

III. 

Details of Pharmacological Action. 

Nux vomica has for a long time enjoyed a favorable reputation 
as a vigorous stimulating agency. Hypodermic preparations of the 
strychnine salts are given more or less indiscriminately in emergency 
cases, not only as legitimate nerve tonics, but too often on the mis- 
taken theory that they are vigorous cardiac stimulants. With strych- 
nine, as with numerous other medicinal agencies, there has been a 
tendency to generalize the use of the drug from insufficient data. 
Strychnine is, as a matter of fact, a tremendous nerve stimulant. 
On the other hand, its use on the heart and circulatory system as 
an emergency stimulant is partially, if not wholly, irrational. 

i. The spinal cord and brain-stem. — With strychnine in thera- 
peutic quantity, up to 2 milligrams of strychnine nitrate, there 
is a great increase in the reflex irritability of the centers of the 
spinal cord and brain-stem. This produces an increase in the sus- 
ceptibility to the ordinary normal stimuli with a corresponding in- 
crease in the volume of discharge of motor nerve impulse. The slight 
acceleration of the cerebral cortex and of the higher nerve centers, 
produced through the action of this factor, is relatively insignificant. 

Strychnine action on the spinal cord seems almost specific, in that 
the effect is selective on the spinal structures. If the brain be removed 
strychnine still produces the same qualitative effects. Reflexes take 
place through the cord in response to milder stimuli than in the 
normal, and there is a tendency to the involvement of larger and larger 
areas of cord until, with toxic doses, even the mildest stimulus enter- 
ing at any sensory point, may set the whole neuro-muscular mechanism 
into tetanic spasms. 

By tetanic convulsions one understands spasmodic and persistent 
contractions of the entire voluntary musculature. The individual 
muscles exhibit series of very rapidly following contractions with 
imperfect relaxations. The usual well coordinated alternate contrac- 
tions of the opposing muscles no longer occur, but instead, the exten- 
sors contract at the same time and stronger than the flexors. The 
effect is that the trunk and limbs are thrown into an extended posi- 
tion. The entire body thus becomes stiff and rigid. The muscular 
cramps involve the respiratory mechanism, hence, when they follow 



98 THE STRYCHNINE GROUP 

each other too rapidly they tend to produce asphyxia. Man and 
mammals usually die after a short series of convulsions, largely be- 
cause of an asphyxial paralysis of the respiratory center. Frogs 
may endure tetanic contractions for days and even weeks, due to the 
fact that adequate respiration is maintained through the skin in 
these animals. 

In attempting to explain the mechanism of the strychnine cramps, 
it has been shown that complete severance of all the sensory nerves 




Fig. 23. — Von Kolliker's scheme of neuron relations in the spinal cord. Orange, 
afferent or sensory ; red, efferent or motor ; and black, central or connecting neurons. 

leads to failure of the development of the spasms. Central stimula- 
tion of the end of a sensory nerve sets up strychnine contractions. 
In like manner, cocainization of the entire skin will eliminate strych- 
nine spasms when the body is otherwise so senstive that even a slight 
current of air is sufficient stimulus to initiate the contractions. It is 
perfectly evident that sensory stimulation is necessary to the develop- 
ment of the tetanic contractions, but that the tetanus does not depend 
upon the toxic change in that mechanism. Houghton and Muirhead ' 

1 Medical News, 1895. 



ACTION ON THE MEDULLA 99 

determined experimentally that strychnine specifically poisoned the 
receptive, i.e., connecting, neurons of the spinal cord. They ex- 
posed the spinal cord of the frog, having excluded the circulation, 
and painted a local area with strychnine solution. The area painted 
soon became hypersensitive, showing the usual general tetanic re- 
sponses to cutaneous stimulation. The tetanus involved, not only 
the local area, but also the motor area of the unpoisoned parts of the 
cord. On the other hand, stimulation of portions of the skin connected 
with an unpoisoned portion of the cord led only to the usual normal 
reflexes. Since direct stimulation of the motor cells themselves can- 
not produce tetanic spasms, it is to be inferred that the toxic influ- 
ence falls especially on the connecting nerves lying between the 
afferent sensory and efferent motor neurons of the cord. The alteration 
of the protoplasm produced in these cells by strychnine does not lead 
to automatic discharge of nerve impulses by the cells in question, 
but the cells are rendered so very unstable that the least sensory 
stimulus sets them into maximal discharges. The nerve impulses are 
strong enough to break down the usual physiological resistance to the 
diffusion through the differential mechanisms of the cord. 

Sherrington x has called attention to the physiological fact that 
the stimuli leading to contractions of the flexor muscles of the body 
are associated with inhibitory processes for extensor muscles, and 
vice versa. Whenever an extensor is reflexly stimulated the flexor 
will be inhibited. In other words the stimulative processes for an 
agonist are associated with an inhibition of the antagonist. Strych- 
nine undoubtedly destroys this normal antagonistic action of the two 
sets of muscles. One may assume that in strychnine tetanus the 
physiological resistances through the cord which maintain the balance 
between the agonistic and antagonistic groups are so broken down by 
the drug that all power of coordinative reaction is lost. 

This general effect of strychnine characterizes the reaction of the 
entire vertebrate series, though the sensibility of the cold-blooded 
animals is considerably less than that of the mammals. 

2. The medulla. — Strychnine produces similar changes in the 
medulla to those noted in the spinal cord, though the cord is more 
sensitive to the drug than the medulla. The nerve centers of greatest 
importance in this connection are the respiratory, the vasomotor, and 
the cardiac inhibitory centers. These are all increased in sensitive- 
ness by the therapeutic action of strychnine, hence give a greater 
volume of response to the usual sensory stimuli. 

Sherrington: Phil. Trans. Royal Society, 1898, Vol. OXC, p. 1G0. 



100 



THE STRYCHNINE GROUP 



3. On respiration. — The influence of strychnine is to increase the 
respiratory activity due to the increased sensitiveness of the respira- 
tory center and the central connecting mechanisms of the cord in- 
volved in respiratory movements. Strychnine is therefore in thera- 
peutic quantity a good antagonist for pathological or pharmacological 
effects which tend to depress the central mechanism of the respiratory 
apparatus. The converse holds under restricted limits only. That is, 
the late or toxic paralysis of strychnine must be guarded against, lest 




Fig. 24. — Sherrington's diagram to indicate the anatomical basis for the physio- 
logical control of stimulative and inhibitive processes in the spinal cord. R. and L., 
right and left pairs of antagonistic muscles. a, <£, afferent paths, which, when 
stimulated, produce coincident stimulations, +, and inhibitions, — , as shown. This 
orderly reaction is broken down by strychnine. 



this stage of its action be additive to that produced by the primary 
acting narcotic. 

4. On the circulation. — Therapeutic doses of strychnine produce 
changes in the circulatory apparatus only by causing variation in the 
delicacy of response in the central portions of the nervous mechanism 
controlling the heart and blood-vessels. This point cannot be too 



ACTION ON THE CIRCULATION 101 

strongly emphasized, owing to the general and often indiscriminate 
practice of administering strychnine in cardiac emergency. 

The heart is indeed influenced in its rhythm and amplitude, but 
only through changes in the reflex sensitiveness of the cardiac centers 
of the cord and medulla. In the otherwise normal animal the heart, 
as a rule, contracts with a somewhat slower rhythm and stronger 
amplitude, typical of increased vagus activity. The changes in the 
heart rhythm under ordinary tonic and therapeutic doses of strych- 
nine, are relatively insignificant; in the subtoxic doses permissible in 
mammalian experiments the heart rate is often markedly slower. 
This statement is applicable to experiments on the otherwise normal 
animal under surgical anesthesia. If a mammal be curarized and 
artificial respiration be maintained, then the variation in cardiac 
rhythm under the influence of strychnine may be demonstrated. 

The curarized animal is especially instructive in other regards. For 
example, in a mammalian experiment, on the animal used in the 
experiment represented in Figure 25, there were intermittent periods 
of very slow cardiac rhythm, alternating with periods of striking accel- 
eration. Considering the fact that strychnine following nicotine and 
atropine, which together eliminate the function of the major por- 
tion of the autonomic system, produces no change in either cardiac 
rhythm or blood-pressure, it is a logical deduction that the drug is 
acting through the controlling nervous mechanisms. Further, strych- 
nine produces its changes through the central portions of these nerv- 
ous mechanisms. Referring back to the alternate retardation and 
acceleration of the heartbeat mentioned above, it is obvious that 
these two nerve mechanisms are both strongly influenced by strych- 
nine, i.e., by action on the centers. Slight variations in external con- 
ditions may give one mechanism the controlling hand at one time, 
the other at another time, since both vagus and accelerator centers 
are known to be in tonic action. 1 

Cardiac muscle, on the contrary, is not only not stimulated, but 
decidedly depressed both in amplitude and rhythm under the influence 
of strychnine. If, for example, the frog's heart be perfused with 
strychnine solution, its rhythm and amplitude are both decreased. 
Following normal perfusion, there is a very slow and prolonged but 
gradual recovery from the toxic effects on the cardiac protoplasm. 
Similar reactions are noted on the isolated mammalian heart. The 
amplitude of its contractions is depressed without a preliminary rise. 

It would seem from the above facts and arguments that the bene- 
a Hunt, Reid: Jour. Exp. Med., Vol. II., p. 151, 1897. 



102 



THE STRYCHNINE GROUP 



ficial effects of strychnine on the circulatory system, that have been 
claimed in therapeutic practice, must rest wholly on the changes 
in the reaction delicacy through the central nervous mechanisms. 
By an increase in the irritability of the cardiac inhibitory and ac- 
celeratory centers, normal stimuli may produce more profound and 
beneficial changes in the musculature of the cardiac apparatus. It 
must be remembered, however, that even this favorable cardiac re- 



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Fig. 25. — The action of strychnine on the vascular nervous complex as shown in 
the blood-pressure and pulse changes. Two experiments, a and b are presented in this 
figure. The experiment was performed on an ether anesthetized dog under the influence 
of curare, and with artificial respiration. Experiment a shows the influence of 
an initial dose of 1 mg. of strychnine injected into the venous system. Experiment 
& represents the effect of a repetition of this dose after several minutes. Between a 
and & the pulse rate varied greatly, showing periods of slow rhythm, as indicated in 
the initial rate in &, interspersed with periods of extremely rapid rhythm. The slow 
rhythm at the beginning of tracing & is due to inhibition. * Gross variations in blood- 
pressure independent of respiratory rhythm occurred. These are well shown in 6. In 
a succeeding test during a period of slow rhythm the vagus nerves were cut, the heart 
rate leaped forward to 210 per minute. The scale to the left measures the pressure in 
experiment a from a zero at the time line at the bottom. The zero and time line of 
experiment 6 falls on the 20 millimeter pressure level of the first experiment, hence, 
deduct 20 millimeters of mercury to read the scale for 6. Time in seconds. New trac- 
ing by Kruse, Boutwell, and Heldt. 



sponse to strychnine is somewhat antagonized by the depression of 
the cardiac muscle tissues. 

In a similar way the vasomotor center is found to be more sensi- 
tive to reflex stimulation when under the influence of strychnine. 
This leads to an increase in blood vascular tone, though the benefit is 
relatively more slight than the changes induced in the heart. In the 
tetanic stage of the reactions of skeletal muscle it is claimed that the 



ACTION ON THE SKELETAL MUSCLE 



103 



vasomotor center is also thrown into tetanic discharge, thus producing 
vascular cramps. A slight rise of blood pressure is usually noted 
during the muscular tetani, a fact also explained on mechanical 
grounds, i.e., through the mechanical pressure changes in the abdomen 
and thorax. My experience is that the mechanical factors play a 
very small part in vascular changes induced by strychnine. This 
fact is borne out by the influence of strychnine after nicotine and 
atropine. Although muscular cramps will be produced as usual, they 
are not accompanied by more than slight mechanical changes in blood- 
pressure. 

5. On skeletal muscle. — The greater volume of muscular con- 
tractions noted in an animal, when under the influence of strychnine, 




Fig. 26. — Strychnine on muscle irritability and muscle work. Little change is 
shown on irritability of the muscle, but the work is increased. Frog 18 grams, dose 
0.1 cc. of 0.1 per cent., allowing 10 minutes for absorption, load 75 grams. Time in 
2 second intervals. New tracing by Summers. 



has generally been explained as due wholly to the influence of the 
alkaloid on the central nervous system. However, parallel experi- 
ments on the amount of work which the isolated gastrocnemii of a 
frog will do under rhythmically repeated stimuli applied directly to 
the muscle, show that the strychninized muscle will accomplish a 
greater amount of work than the normal muscle. In fact, the muscle 
substance becomes somewhat more sensitive to stimuli ; in other words, 
the minimal stimulus on the drugged muscle is reached by a stimulus 
of weaker intensity. It has not yet been clearly shown whether the 
muscle substance or the " receptive substance " is really the point of 
favorable action. In the toxic stage strychnine produces a paral- 
ysis of the motor end plates in a way comparable to curare, with 
which the drug is chemically related. This last point suggests that 



104 THE STRYCHNINE GROUP 

the receptive substance may be the point stimulated in the therapeutic 
dosage. 

6. Action on the special sense organs. — Experimentation has 
produced cumulative results indicating a definite beneficial influence 
on the sensitiveness of the special sense organs. The sense of smell is 
rendered more acute, and a change in the character of odors has been 
noted. In the same way the senses of sight and of hearing are 
rendered more acute, the usual tests of hearing are perceived at a 
greater distance than normally, and the visual field is enlarged. The 
sense of touch is rendered more delicate. This increase in delicacy 
is noted both in relation to the strength of the threshold of the 
stimulus and in the accuracy of localization. However, it is not clear 
just what portion of the sensory mechanism is acted upon by the drug. 
We are inclined to believe that the change is chiefly, if not wholly 
central rather than peripheral, though unilateral action claimed for 
the eye cannot be explained by this view. 

7. On the alimentary canal. — Strychnine has long enjoyed a 
reputation as a bitter tonic. This is due primarily to the extremely 
bitter taste, which can be detected one part in 600,000, but there is a 
factor of systemic action involved. The bitter taste leads to pro- 
found physiological reflexes involving the mouth and gastric glands, 
also the motor apparatus of the stomach. When strychnine is ab- 
sorbed, even in extremely small quantity, the secretory and gastric 
motor mechanisms of the central nervous system are rendered more 
susceptible to stimuli, hence an increase in tone results. The general 
influence on metabolism, especially of sluggish tissues, as in vascular 
and in alimentary atony, is favorable. 

8. On metabolism. — Since strychnine produces a general rise in 
tonus of the neuro-motor mechanisms of the body and increases the 
volume of response to the usual stimuli, it is obvious that it will pro- 
duce a general rise in metabolic activity. There is a tendency to a 
rise of body temperature, though it is controlled by the heat regu- 
lating mechanism. The increased metabolism is secondary rather than 
primary. Hence skeletal muscle, the plain muscle, and the glands 
are thrown into greater activity through the greater delicacy of poise 
of the centers of the central nervous system. 

Strychnine is fixed by the tissues of the body, probably by the 
lipoids. Koch suggests that the intensity of action of strychnine 
bears a relationship to the percentage of lipoids in the particular 
tissues most strongly influenced by the alkaloid. 

9. Excretion. — Strychnine is excreted unchanged in the urine, 



STRYCHNINE POISONING 105 

although a portion is greatly delayed in its excretion, due to its fixa- 
tion in the tissues, and a proportion is ultimately oxidized. This 
latter point was established by Meltzer, who found that nephrectomized 
rabbits were able to withstand strychnine in toxic amounts, provided 
it were given in broken doses. 

IV. 

Strychnine Poisoning. 

The too frequent cases of strychnine poisoning make it desirable 
to discuss the antidotes and treatment. Accidental and suicidal 
poisoning usually occurs by the method of taking the drug into the 
stomach. The first step then is to produce evacuation of the stomach, 
either by vomiting or by means of the stomach pump. Precipitants 
such as tannic acid or strong tea may be given for temporary fixation 
of the strychnine, but this must be removed just the same. Strych- 
nine is not readily absorbed from the stomach, but disappears readily 
when it reaches the intestine. After convulsions have begun or are 
approaching, it may be very difficult to introduce the stomach tube. 
A slight spray of cocaine in the mouth-pharynx region is beneficial 
or ether or chloroform may be given lightly, in order to pass the tube. 

Evacuation of the stomach should be followed up with systemic 
treatment, which consists in the use of antagonists, such as ether or 
a small quantity of chloral. Ether is preferable to morphine because 
of the greater ease of its control. Chloral and morphine by their 
prolonged action become dangerous in the paralytic stage of strych- 
nine action. 

Meltzer has recently emphasized the value of artificial respiration 
in strychnine poisoning. The administration of large quantities of 
fluid and of diuretics is favorable, though the excretion of strychnine 
is relatively slow at best. 

Brucine. 

Brucine has an action very similar to that of strychnine except 
that it is much weaker. It requires a dose of brucine about fifty 
times larger to produce similar effects. In one regard, brucine is 
relatively more toxic, namely, in its curare-like paralysis of the motor 
nerve endings. 

Thebaine, one of the alkaloids of opium, it must be remembered, 
has also an action similar to strychnine. It also brings on strychnine- 



106 THE STRYCHNINE GROUP 

like spasms, though these spasms come somewhat later and are less 
intense. 



Condensed Summary of the Action of Strychnine. 

Strychnine is a convulsant alkaloid, acting primarily on the cen- 
tral nervous axis and specifically on the connecting neurons between 
the sensory and motor neurons. Its action falls most heavily on the 
spinal cord, and on the medulla. In therapeutic quantity it produces 
great increase in the reflex irritability of the cord and of the great 
vital centers of the medulla. It has a slight though important similar 
effect on the higher portions of the brain and cortex. In toxic dose it 
breaks down the central resistance so that the mildest of sensory 
stimuli produce profound and general tetanic contractions of the 
entire skeletal musculature. The smooth muscle of the circulatory 
system and of the alimentary tract take little part in the tetanic 
cramps. 

Respiration is accelerated, the heartbeat somewhat slowed, and 
the vasomotor tone somewhat increased — all due to increase in sensi- 
tiveness of the corresponding nerve centers. The rhythm and ampli- 
tude of heart muscle are both decreased without preliminary stimula- 
tion. Hence beneficial cardiac tonic effects do not occur directly, 
though there are some favorable actions on the nervous mechanisms, 
chiefly the vasomotor. Skeletal muscle (of the frog) is more sensi- 
tive after strychnine and yields larger contractions to normal stimuli. 
Motor endplates are paralyzed by the toxic dose. 



C. Drugs with Specific Action for Peripheral Parts of the 

Nervous System. 

CHAPTER XL 

THE CURARE GROUP. 

I. 

Historical and Chemical. 

The South American Arrow Poison, Curare, stands as an example 
of a series of toxic preparations that have long been known by the 
aboriginal inhabitants of the northern portion of the South Ameri- 
can continent, especially the valley of the Amazon. At the time of 
the earliest explorers these people were using arrow poisons, both in the 
hunt and in war. Efforts have been made by whites to discover the 
exact plants from which these concoctions were made, but the matter 
has been made difficult by the fact that the Indians hold the prepara- 
tions secret. 

The toxic principles are apparently derived, almost exclusively, 
from members of the Strychnos family, of which Strychnos toxifera 
and Strychnos castelnasa are the chief. Boehm has isolated several 
toxic principles, curine C 18 H 19 N0 3 , tubocurarine, C 19 H 21 N0 4 . The 
former is slightly different in its action, while the latter produces the 
results typical of the crude preparations. Both are strongly toxic. 
The native preparations are put up in containers typical of the differ- 
ent localities. Boehm 1 has examined these preparations and finds 
that they contain, in different proportions, a number of related alka- 
loids. Beside the above may be mentioned protocurine, C 20 H 23 NO 3 , 
protocuridine, C 19 H 21 N0 3 , and protocurarine, C 19 H 25 N0 2 . These alka- 
loids readily form crystalline acid salts. 

II. 

Outline of Pharmacological Action. 

1. Specific paralysis of the motor nerve endings in skeletal muscle. 

2. Paralysis of the pre-post ganglionic synapses of peripheral 
ganglia when large doses are used. 

1 Boehm: Festschrift zu Carl Ludwig's 70. Oeburtstagc, 1886. 

107 



108 THE CURARE GROUP 

III. 

Details of Pharmacological Action. 

i. Specific action on the motor nerve endings. — Curare owes its 
physiological action almost exclusively to the specific toxic paralysis 
of the connecting substance, linking motor endings and skeletal 
muscle. This fact was demonstrated in the middle of the last century 
by Claude Bernard, 1857, by the method which has become classic in 
physiological literature. The method slightly modified as now prac- 
ticed is: First, shut off the circulation in one leg of the frog by a 
ligature around the thigh, excluding the sciatic nerve; second, in- 
ject curare into the lymph sacs and allow absorption to take place, 
whereby the alkaloid passes into the general circulation, going into 
all parts of the body with the exception of the muscles and tissues 
of the ligated leg. Paralysis of all the voluntary mechanisms takes 
place. The point of action of the drug is demonstrated by the follow- 
ing steps in the physiological analysis : 

1. Stimulation of the sciatic nerve of the curarized leg produces 
no contraction of its muscles. 

2. Stimulation of the sciatic nerve of the unpoisoned side below 
the point of the ligature naturally produces contractions, since no 
drug has come into contact with this part of the apparatus. 

3. Stimulation of the sciatic nerve of this side above the ligature, 
where the nerve has been irrigated by the blood containing the curare, 
also produces contraction of the muscle, showing that the nerve 
fibers are not directly poisoned. 

4. Upon direct stimulation of the muscle of the poisoned leg 
contraction results, demonstrating that the curare has not paralyzed 
the contractile muscle substance. 

Bernard drew the conclusion that the toxic effect is upon the 
protoplasmic substance of the motor end plates, for which, therefore, 
the poison is specific. 

Kuhne later, 1886, gave a beautiful demonstration in this way: 
He noted that the motor nerve of the gracilis muscle of the frog 
branches before it enters the muscle. By cutting the muscle between 
the two branches a double preparation is secured, in which the 
parts are innervated by one nerve, but the end plates and muscle 
substance form two physiologically separate preparations. When 
curare is painted on one preparation stimulation of the common 
nerve fails to produce contraction in that division only. When the 



CURARE ON PERIPHERAL GANGLIA 109 

poisoned muscle, with its contained nerve filaments, is stimulated 
and recurrent conduction carries the nerve impulse around, and 
never fails to produce contractions in the unpoisoned slip. Exces- 
sive use of curare later destroys the irritability of these nerve fila- 
ments, indicating that nerve fiber does ultimately succumb to the 
poison. 

Langley x has more recently examined the point of action of curare. 
He argues that the poison is not toxic to the nerve endings, but 
rather is toxic to a differentiated secondary constituent of the muscle 
fiber, which he designates the " receptive substance," a substance 
that receives the stimulus from the nerve and transmits it to the 
proper contractile substance. Strength is given his position by the 
fact that curare antagonizes certain muscle-stimulating substances 
after motor nerve degeneration occurs. 

Bernard showed also that the sensory mechanism of the reflex arc 
is not injured by ordinary doses of curare. Stimulation of the skin 
on the poisoned side of the curarized frog leads to reflex contraction 
of the muscles of the unpoisoned leg. If the sensory nerves in the 
skin were paralyzed such a reaction would be impossible. 

2. Curare on peripheral ganglia. — Strangely enough curare does 
not poison the striated muscle of the heart, though large doses do 
eliminate the function of the vagus nerve. This effect is accom- 
plished by a poisoning of the pre-ganglionic connections around the 
cells of the cardiac ganglia, a nicotine-like effect. Other autonomic 
ganglionic endings are similarly poisoned by large doses of curare, as, 
for example, the vasomotor paths, the secretory nerves of the salivary 
glands, and the nerves controlling the muscles of the iris and ciliary 
apparatus. 

Curare leads to a fall of blood pressure in the mammal because 
the paralysis of the pre-ganglionic endings eliminates vasomotor 
tone. Such effects are not very profound, nothing comparable to the 
intensity of action on the skeletal motor nerve relations. 

3. Absorption of curare from the stomach. — It has long been 
known that curare is comparatively inactive when taken by way of 
the stomach. There is a sharp contrast as between the intensity and 
rapidity of action from subcutaneous administration. Hence its 
inertness in the stomach has called for explanation. Several views 
have been offered, but that of Bernard is most probable and would 
account for the facts. Bernard's view is that the absorption takes 
place so slowly from the stomach and that the active principle of 

1 Langley, J. N.: Journal of Physiology, Vol. XXXIIL, p. 374, 1905. 



110 THE CURARE GROUP 

the drug is excreted so rapidly that its toxic effects do not materialize. 
Some evidence has been found to show that curare is destroyed either 
by the digestive action of the stomach or by the changes that occur 
during absorption. Another factor enters here, namely, the fact 
that the venous blood from the stomach passes through the liver 
where the parenchyma tends to fix this alkaloid as it does many others. 
This would hold back the passing of curare into the general circula- 
tion, hence would be favorable to its elimination before a fatal toxic 
action took place. 

IV. 

Comparison of Curare with Related Drugs. 

Curare stands at one end of the series of drugs and nicotine at 
the other as follows : 

Nicotine, coniine, gelseminine, sparteine, curare 

Ratio of stimulating effect on the central nervous system and of paralysis of 

peripheral ganglia. 

< 



> 

Relative toxicity to peripheral nerve endings. 

Nicotine produces preliminary stimulation of considerable in- 
tensity followed by marked paralysis. Curare produces practically 
no central stimulation. Nicotine has slight effect on peripheral 
nerve endings. Curare has pronounced and specific toxic effects on 
the endings (or receptive substance) of skeletal muscle. Nicotine 
and curare both are toxic to peripheral ganglia, though nicotine is 
much more toxic than curare. 

There are a number of drug groups which have characteristic 
actions on peripheral parts of the nervous mechanism, and some- 
times on particular motor nerve tissues. These drugs interfere with 
physiological activity by a selective combination with the differ- 
entiated structures of some portion of the parts of the body involved. 
They are in the highest degree specific in action. Their specificity 
depends upon a greater chemical affinity with the physiologically 
differentiated constituents of certain morphological structures. It is 
not to be understood that the reaction is limited exclusively to these 



COMPARISON" OF CURARE WITH RELATED DRUGS 111 

parts and that other portions of the body are inert toward the drug, 
but rather that the degree of selection depends upon the greater 
intensity of action at some particular morphological point. In the 
therapeutic use of such drugs it is comparatively easy to accom- 
plish a change in the function of the part specifically attacked great 
enough to be of clinical value without materially interfering with the 
functions of other non-specific reacting parts of the body. Of this 
series the most characteristic from the pharmacological point of view 
are atropine, nicotine, coniine, curare, and the pilocarpine series. 



CHAPTER XII. 
THE ATROPINE SERIES. 

I. 

Historical and Chemical. 

The atropine series contains a number of alkaloids of extremely 
bitter taste, found in the plants of the order Solanaceae. Of the 
species yielding alkaloidal principles should be mentioned Atropa, 
Datura, Duboisia, Hyoscyamus, etc. 

Atropa belladonna, deadly nightshade, contains atropine, hyos- 
cyamine, and hyoscine. 

Datura stramonium, or thorn apple, contains atropine, hyoscya- 
mine, and hyoscine. 

Duboisia myoporoides, contains duboisine and hyoscine. 

Hyoscyamus niger, or henbane, contains atropine, hyoscyamine, 
and hyoscine. 

Mandragora autumnalis, or mandrake, contains mandragorine, and 
hyoscyamine. 

Atropine itself is extracted chiefly from the roots and leaves of 
the plant Atropa belladonna. It is associated with hyoscine and 
hyoscyamine. 

The drug is readily decomposed into tropine and tropic acid. 
Hyoscyamine is isomeric with atropine; in fact, atropine is now con- 
sidered to be a mixture of dextro- and levo-rotary hyoscyamine. The 
chemical relationship of the elements is expressed in the formula : 

Ha H H 2 

C C C CH 

C 17 H 23 N0 3 = >NCH 3 >CHO- CO- CH 2 OH 

/ / I 

C C C GeHs 

H 2 H H 2 

Atropine Tropine Tropic acid 

II. 

Outline of Pharmacological Action. 

1. Paralysis of the peripheral endings of the secretory nerves, 
the cardiac inhibitory nerves, the constrictor nerves of the pupil, and 
of the motor nerves of the stomach and intestine. 

112 



DETAILS OF PHARMACOLOGICAL ACTION 113 

2. Initial stimulation of the motor apparatus of the alimentary 
canal and urinary bladder, thought to be muscular. 

3. Mild initial stimulation of the cerebral cortex and of the cen- 
ters of the brain-stem and cord, followed by depression and later by 
paralysis. 

4. Toxic direct paralysis of the medullary centers. 

III. 
The Details of Pharmacological Action. 

Other alkaloids of the atropine series differ in their effects from 
atropine only in a mild quantitative way. Hence the description of 
atropine will serve as a type for all the members of the series. 

i. General symptoms of the action of atropine. — The therapeutic 
dose of atropine is from 0.5 to 1 milligram. These or slightly larger 
doses produce in man a perceptible acceleration of the heartbeat, a 
mild dilation of the pupil, a general dryness of the throat and 
skin, accompanied by difficulty in swallowing, thirst, and general 
discomfort from the lack of secretions of the mouth and naso- 
pharyngeal region. If the symptoms are severe there is nausea, oc- 
casionally dizziness, and general mental discomfort. 

There is an initial slight increase of cerebral functions, which 
passes into incoherence, garrulousness, delirium, or semi-consciousness, 
but without loss of muscular control. In extreme cases there may be 
convulsions. In toxic conditions this effect may be followed by deep 
stupor, labored respiration with a tendency to asphyxiation, and even 
asphyxial death. This general picture is complicated by the specific 
peripheral effects of atropine expressed in combination with those on 
the central nervous system. 

2. Action of atropine on the central nervous system. — The evi- 
dences of stimulation and excitement with the respiratory and circula- 
tory disturbances indicated above show that atropine has a profound 
influence on the central nervous system. Unlike caffeine, which acts 
primarily on the higher cortical centers, and strychnine, which acts 
earliest on the spinal cord, atropine produces its effect through a 
general more uniform action on the whole nervous system — a little 
more profound on the medulla, if any distinction is to be drawn. 
In the later or more intense stages of atropine action, the motor side 
of the central nervous mechanism is the more profoundly influenced, 
and it is this that leads to increased physical activity, garrulousness, 
or convulsions. In animal experimentation one rarely observes 



114 



THE ATROPINE SERIES 



cortical nervous accelerator effects due to atropine. Yon Bezold and 
Blobaum * first established the stimulating action of atropine upon 
the respiratory center. They injected atropine peripherally into 
the carotid artery, so that the alkaloid was first brought into 
direct contact with the central nervous mechanism. They noted an 
immediate quickening of respiration. This effect would seem to 




Fig. 27. — Diagrammatic representation of the nerves of the intrinsic muscles of the 
eye. Sup. Corp. Quad., superior corpora quadrigemina. Xuc. Ill, nucleus of the third 
cranial nerve. Sup. Cerv. G., superior cervical ganglion. Circ. M., circular muscles of 
the iris. Rad. M., radial muscles of the iris. Ciliary G., ciliary ganglion. 



follow from the direct action of atropine upon the respiratory center, 
a fact that has been confirmed. There was also an increase in the 
respiratory volume of from 100 to 300 per cent. The primary effects 
of atropine are followed by a deep depression of function with ulti- 
mate paralysis of the central nervous system. The paralysis of the 
respiratory medullary center may, if artificial respiration is main- 
tained, be overcome. The life of the animal is thereby prolonged, and 
the recovery, if it occurs, is due to the fact of rapid oxidation of 
atropine by the tissues. 

3. The specific action of atropine on the eye. — Atropine applied 
to the eye locally produces dilation of the pupil and loss of the power 
of accommodation. The toxic systemic effects on the respiratory 
center are produced before complete loss of function of the accom- 
modating mechanisms occurs, hence in practical ophthalmology it is 

1 Von Bezold and Blobaum: v. Bezold's Untersuchungoi, Vol. I.. 1ST". 



ACTION ON GLANDS 115 

customary to apply atropine by dropping it on the surface of the eye 
in a one per cent, solution. After about 15 minutes the effects are 
maximal and last for many hours. 

The ciliary mechanism and the iris of the eye are innervated by 
two sets of nerves, as shown in the Figure 27. The third cranial or 
oculomotor nerve distributes branches to the muscles of the ciliary ap- 
paratus, and the circular muscles of the iris. Stimulation of this 
nerve leads to an act of accommodation adjusting the eye for near 
vision, and to a constriction of the pupil. The cervical sympathetic 
also distributes branches to the eye. These innervate the radial 
muscles of the iris and produce dilation of the pupil when stimulated. 

The loss of the power of accommodation from local application 
of atropine is explained on the ground of a toxic paralysis of the. 
nerve endings of the oculomotor fibers on the ciliary muscles. 

The dilation of the pupil can be accomplished physiologically by 
either of two methods: contraction of the radial fibers through 
stimulation of the cervical sympathetic nerve, and relaxation of the 
circular fibers by elimination of function of the oculomotor. A direct 
paralysis of the circular muscles in the absence of effect on the radials 
would, of course, accomplish a dilation of the pupil. That atropine 
does not poison the muscles themselves can be easily shown by the re- 
sponse of the muscles of the iris to stimulation by the direct applica- 
tion of electrodes. It would seem, therefore, that in the local applica- 
tion of atropine to the eye the functional disturbance is due to paral- 
ysis of the oculomotor nerve. Direct stimulation of the oculomotor 
nerve either proximal or distal to the ciliary ganglion, is no longer 
effective after the application of atropine. This indicates a poisoning 
in the junction between the nerve and the muscle, according to 
Langley's views at the " receptive substance." 

The paralysis of the nerve endings of the ciliary mechanism of the 
eye by atropine persists for two or three days, and often for six to ten 
days in the case of the iris. The artificial alkaloid, homatropine, 
produces the same ocular effects, but is not so persistent, hence is 
to be preferred under certain therapeutic conditions. 

4. The specific action on glands. — The dryness of the mouth 
and throat produced by atropine is due to a decrease in the secretions 
of the salivary and other buccal glands, as well as those of the throat. 
Atropine accomplishes this effect by an elimination of the control 
of the secretory nerves. Since direct stimulation of the chorda 
tympani or of the tympanic branch of the hypoglossal produces no 
secretion of the salivary glands, it is apparent that the action of 



116 THE ATROPINE SERIES 

the drug is peripheral. The stimulation of the cervical sympathetic 
in the dog still produces its scanty secretion after atropine. Here, 
therefore, as in the eye, only one set of nerves is paralyzed, and that 
by a toxic elimination of the function of the terminal nerve endings 
and not by paralysis of the gland cells. 

Other glands have their secretion diminished by atropine, es- 
pecially the gastric, pancreatic, and to a much less extent the mam- 
mary glands. Thanks to the work of Pawlow, we now know that the 
gastric glands produce their secretion under a well-coordinated 
nervous control. The vagus is proven to be the secretory nerve for 
the gastric glands. Atropine produces a profound inhibition of gastric 
secretion, both in the Pawlow dog and in man (Riegel). 

In like manner atropine in weaker doses inhibits the pancreatic 
secretion. Modrakowski 1 has emphasized the fact that very large 
doses of atropine in the dog call forth a voluminous pancreatic secre- 
tion — a fact difficult of explanation by the laws of nerve control. 
The secretion of pancreatic juice, which is controlled through the 
hormones, indicates that hormone reaction, in general, is not inter- 
fered with by atropine. 

In the case of the secretion of milk, the therapeutic action of 
atropine is demonstrated clinically, though in the present state of 
our knowledge of the physiological mechanism of the mammary 
glands, it is not fully understood what structure the atropine affects. 
The development of these glands and of lactation at parturition are 
phenomena dependent on hormone actions, and are quite independent 
of nerve control, as is now well known. 

Atropine paralysis occurs in the nerves of the sweat glands. 
Langley has shown that the sciatic nerves contain secretory fibers 
for the sweat glands of the foot of the cat and the dog, where he 
has mapped their distribution. After atropine poisoning these nerves 
no longer induce secretion. It follows that atropine must be toxic to 
the nerve endings of the sweat fibers. 

5. On the circulatory system. — There is a slight rise of blood- 
pressure following atropine, together with an increase in the rate 
of the heart. Experimental investigations of the peripheral circula- 
tion show that atropine has little effect on the size of the arterioles, 
except in toxic concentrations. There is a reddening of the skin, 
with evident vascular dilation just at the beginning of its systemic 
action, whether due to a paralysis of the vasoconstrictor center or a 
stimulation of the vasodilator center is not yet determined. In ex- 

1 Modrakowski : Pfluger's Archiv, Vol. CXIV., p. 487. 



ACTION ON THE CIRCULATORY SYSTEM 



117 



periments on the salivary glands the stimulation of the chorda 
tympani, which contains vasodilator fibers, produces an increased 
flow of blood through the glands, though the increase is not associated 
with a secretion of saliva. This well-known experiment shows that 
the endings of the vasodilator nerves are not paralyzed, but are active 
in the presence of an amount of atropine toxic to the secretory 
endings. 

On the other hand, the nervous mechanism of the heart is pro- 
foundly influenced. /Atropine produces an elimination of the in- 



<%^ajG^<*J«f^. 



Ct»~MiUU,-2.9«4. 






SSBBBG 



Fig. 28. — Stimulation of the chorda tympani after the administration of 10 mg. 
atropine. The carotid pressure, lower line ; volume of suh-maxillary gland, second line 
from the top. The volume of the gland increased, showing that atropine does not 
eliminate the vaso-dilator nerve function. After Bunch. 

hibitory control of the vagus over the heart. ) When atropine is given 
systemically the vagus control is lost, and the heart is accelerated in 
the same way as though the vagus nerves were sectioned in the neck. 
Whereas stimulation of the peripheral end of the vagus nerve in the 
normal animal produces more or less inhibition of the heart, after 
atropine such stimulation of the vagus, and indeed of the region of 
the sinus, is without influence on the heart, showing a loss of the 
vagus control at the neuro-muscular unions.) Therapeutic doses of 
atropine have little accelerator effect on the heart rate of very young 
animals or of young children, due to the fact that the vagus tone 
is less developed in the young. 

The heart muscle itself is very little affected by atropine. In 
isolated muscle preparations from the terrapin's heart a wide range 
of concentration of atropine in solution in physiological salines may 



118 



THE ATROPINE SERIES 



be applied to the tissue with little or no effect on the rate. There is 
much irregularity in the results, but the accelerations are about bal- 
anced by the depressions which occur. Doubtless it is these irregu- 
larities that have led to the contradictory statements that have 




Fig. 29. — Diagrammatic representation of the origin and course of the cardiac nerves 
in the dog, showing the constituent neurones. Dl-5, first to fifth dorsal spinal nerve. 
Inhibitory fibers in blue, accelerators in red. Modified from Moret. 



appeared in the literature concerning the effects of atropine on the 
cardiac muscle. 

6. Atropine on the alimentary canal, the stomach. — The peri- 
stalses of the stomach are under the control of the vagus, which is the 
motor nerve for this organ. Atropine produces an inhibition of the 
contractions. Minute doses apparently are not entirely toxic to the 
local nervous mechanism, but they do * eliminate, at least depress, the 



THE BLADDER AND UROGENITAL APPARATUS 119 

motor control of the vagus endings. The preponderant inhibitory 
tone of the splanchnic apparatus in the absence of the motor activity 
of the vagus leads to a cessation of the gastric peristalses, a fact of 
especial therapeutic interest in the practical use of this drug. 

The intestine. — The motor apparatus of the intestine is also 
paralyzed by atropine, though there is some contradiction in the 
literature in this case. Very small therapeutic doses occasionally 
increase peristalsis by stimulation of the smooth muscle (Jacobj), 
or of the ganglion cells like nicotine (Langley and Magnus). In a 
general way atropine reacts on the intestine in much the same way 
as on the stomach. Meltzer and Auer 1 say, " Atropine frequently 
abolished completely the vagus effect upon the stomach and reduced 
greatly its effect upon the intestines." 

7. On the bladder and urogenital apparatus. — The urinary 
bladder and the uro-genital system are controlled through nerves 
arising in two different regions of the spinal cord. One set arises from 
the lumbar region, the fibers passing out in the third to the fifth 
ventral roots of the lumbar nerves. They run thence through the 
sympathetic chain and hypogastric nerve. The other nerves arise 
from the lower sacral cord, the second to the fourth sacral nerves, and 
run to their distribution by way of the nervi erigentes. 

Langley and Anderson 2 found variations in the physiological 
responses of the uterine walls given in different animals when the 
hypogastric nerves were stimulated. Dale 3 later demonstrated that 
upon stimulation of the hypogastric in the non-pregnant cat there 
was generally a relaxation of the muscular walls of the uterus. But 
in the rabbit sometimes there was relaxation and sometimes contrac- 
tion of the muscles. If the test was made on a pregnant animal the 
response was always a contraction of the muscular walls, sometimes 
followed by peristalsis. In the male the muscular walls of the 
vasa deferentia and seminal vesicles are set into contraction by the 
stimulation of the hypogastric nerve. It will be remembered that 
this nerve contains the vasoconstrictor fibers for the blood-vessels of 
all these organs. Atropine does not abolish the functional nerve con- 
trol of the uterus on the one hand or of the seminal vesicles on the 
other. 

1 Meltzer and Auer: American Journal of Physiology, Vol. XVIL, pp. 143-166, 
1906. 

•Langley and Anderson: Jour. Physiol., Vol. XIX., p. 127, 1895. 

•Dale, H. H.: Jour. Physiol, Vol. XXXIV., p. 189, 1906. See also Cushny: 
Jour Physiol., Vol. XXXV., p 1. 



120 THE ATROPINE SERIES 

The innervation of the bladder is twofold. Fibers reach it by 
way of the hypogastrics as mentioned above, and through the nervi 
erigentes. Stimulation of the hypogastric leads to contraction of 
the muscular walls of the bladder, chiefly of the sphincter. The sacral 
nerves, i.e., the nervi erigentes, it will be remembered, are the special 
paths of vasodilator fibers. They also supply motor fibers to the 
bladder as well as to the constrictor urethrae. " The sacral nerves 
cause contraction of all the muscle fibers of the bladder, whether they 
are circular, oblique, or longitudinal. ' ' 

Langley and Anderson question the presence of inhibitory fibers 
in the muscular walls of the bladder, stating that " few, if indeed 
any, exist." Atropine in large doses acts to reduce the sacral 
motor control over the bladder, apparently acting in a way compa- 
rable to its influence on the nervous control of the stomach and 
intestine. It does not completely eliminate the nerve control, that 
is, it does not completely poison the endings. The depressing effects 
produced, even with comparatively large doses, are not very great, 
not enough to eliminate the nervous control. There is indeed a 
slight but questionable stimulation of the smooth muscle and possibly 
of the nerve centers of the cord after mild therapeutic doses of 
atropine. In the urinary bladder, especially in the hypersensitive 
conditions, which occasionally occur in children, this atropine quies- 
cence leads to a better retention of the urine. In the uterus atropine 
suspends peristaltic contractions. It is not clear just what phase of 
the nerve-muscular mechanism is primarily influenced by the atropine, 
but the present tendency is to assume a similarity of action to that 
which occurs in other better known physiological mechanisms, as, for 
example, the eye. 

8. Atropine excretion. — Atropine is excreted through the kidney. 
It has been shown by Fleischmann, 1910, and confirmed by Metzner, 
1912, that atropine is destroyed by the blood of the rabbit, even in 
mixtures in the test tube. Atropine breaks down into tropine and 
tropic acid. This capability probably accounts for the fact that the 
rabbit is able to resist such large quantities of atropine. However, 
this animal may have acquired some degree of immunity from eating 
plants of this series. 

IV. 

Condensed Summary of the Pharmacological Action. 

The changes in physiological reaction in the human body upon the 
introduction of atropine are relatively complex because of the num- 



SUMMARY OF PHARMACOLOGICAL ACTION 121 

erous secondary disturbances of the physiological balance. In small, 
i.e., therapeutic doses, there is a dryness of the mouth and throat 
from a decrease in secretions, a slight increase in physiological reac- 
tions through the nervous system, excitement followed by a tendency 
in the toxic stage toward irrational mental reactions, with garru- 
lousness, unconsciousness, and even convulsions, followed by stupor 
and paralysis. Respiration is accelerated slightly, then depressed 
and stopped by central paralysis. Blood-pressure is at first in- 
creased, through stimulation of the regulative nerve centers, the 
heart shows initial very slight inhibition, followed by increased rate 
of beat from terminal paralysis of the vagus. There is little direct 
effect upon heart muscle. The blood-vessels in the toxic stage are 
dilated and blood-pressure falls. The general voluntary motor ap- 
paratus is finally depressed and paralyzed through action on the 
motor nerve cells. Atropine produces a slight initial stimulation of 
smooth muscle in various localities, followed by a depression of peri- 
staltic contractions. This is true for the intestine, urinary bladder, 
and uterus. 

Scopolamine or hyoscine has a greater depressor effect upon the 
various portions of the central nervous system and the autonomic 
nerve centers. It enjoys a certain amount of prestige in cases of 
mania, and also as a depressor of hyperexcitable sexual centers. 



CHAPTER XIII. 

THE PILOCARPINE, MUSCARINE, PHYSOSTIGMINE 

GROUP. 

Under this head may be included a series of active alkaloidal 
principles which have a strong peripheral stimulating effect. In, 
the main these drugs produce their action at the point of nerve term- 
inations in differentiated tissues. 



I. PILOCARPINE. 

I. 

Historical and Chemical. 

Jowett * has shown that the leaves of Pilocarpus jaborandi and of 
other species of the genus contain only three alkaloids, pilocarpine, 
iso-pilocarpine, and pilocarpidine, the last named only in small 
quantity. Harnack and Meyer 2 have given us the composition of 
pilocarpine, but the structural formula is quoted from Marshall : 

C n H 16 N a 2 = C3H5CH-CH.CH2C-N.CH3 

CO CH 2 CII-N,/ 011 



O 

Pilocarpine (Marshall) 



II. 

Outline of Pharmacological Action. 

1. A strong stimulation of glandular structures — the salivary, 
bronchial, lachrymal, and gastric glands, and the liver. 

2. A similar stimulation of the s7nooth muscle of the eye, of the 

Jowett: Jour. Chem. Soc, 1900, Vol. LXXVIL, pp. 473, 851; 1901, Vol. 
LXXIX., pp. 580, 1,331; 1903, Vol. LXXXL, p. 438. 

2 Harnack and Meyer: Arch. f. Exp. Path. u. Pharm., 1880, Vol. XII., p. 366. 

122 



DETAILS OF PHARMACOLOGICAL ACTION 



123 



alimentary tract, the urinary bladder, the spleen, and of the bronchi, 
but little or no stimulation of the muscles of the blood-vessels. 

3. A slight stimulation, followed by marked depression, of the 
centers of the central nervous axis. 

III. 

Details of Pharmacological Action. 

i. The stimulation of the glands. — In therapeutic dose, 5 to 8 
mgr. for man, pilocarpine leads to a marked increase in the secretions. 






Parotid 
3 




Fig. 30. — Diagrammatic representation of the neurones in the innervation of the 
salivary glands. V, VII, and IX, the corresponding cranial nerves. Ch. T., chorda 
tympani containing secretory and vasodilator fibers, also, according to certain author- 
ities, gustatory nerve fibers ; Tym. Br. 9th } tympanic branch of the 9th cranial nerve 
containing secretory and vasodilator fibers for the parotid gland ; Otic O., Otic gan- 
glion ; Ling., lingual branch of the 5th ; Sup. C. O., superior cervical ganglion of the 
sympathetic; 8. M. G., submaxillary ganglion. Some of the neurones through this 
ganglion belong to the sublingual gland. PreganglTonic neurones in red, also the central 
neurone in the cord. Postganglionic neurones and sensory neurones in black. Diagram 
based on figures by Sheldon, Brubaker, and Starling. 



These are most striking in the salivary glands, sweat glands, and the 
mucous glands of the mouth and throat. The gastric and pancreatic 
secretions are also increased. The liver produces an increased 
amount of sugar, leading to glycosuria, which suggests that this organ 
too is stimulated by the pilocarpine. 

The amount of saliva and of perspiration produced is enormous, 



124 



PILOCARPINE, MUSCARINE, PHYSOSTIGMINE 



amounting to several hundred cubic centimeters more than the normal. 
Ewing x has made a special study of the quantity and chemical com- 
position of the saliva in man produced under the stimulus of pilocar- 
pine. He records an instance in which a normal 15-minute secretion 
of 37 cc. of saliva was increased to 563 cc. in the third 15-minute 
period after 10 mgrs. of pilocarpine. He also demonstrated that the 




Fig. 31. — Influence of 0.2 mg. pilocarpine on the rate of secretion of saliva. The 
drops of saliva are recorded in the second line from the top. At a injection of pilocar- 
pine, at b injection of 50 cc. of oxygenated blood. From Jonescu. 

total amount of solids, both organic and inorganic, keeps pace with 
the increase in the total secretion. 

The glands are stimulated through the nervous mechanism. Since 
the secretion occurs after section of the nerves but is absent when 
the nerve endings are paralyzed by atropine, it is assumed that the 
pilocarpine reacts with the substance of the terminations of the 
nerve fibers, as has been advocated by Langley. 2 However, Langley 
has more recently arrived at the conclusion that pilocarpine reacts 
with a differentiated portion of the gland cell, the " receptive sub- 
stance/ ' which is the linking up substance as between the fibrils and 
the secreting gland substance. He finds that the sweat glands of the 
foot produce secretion after sectioning of the sciatic nerve. 

The kidney and the mammary glands are not particularly influ- 



1 Ewing, E. W.: Jour. Pharm. and Exp. Ther., 1912, Vol. III., p. 1. 

'Langley, J. N.: Journal of Physiology, 1905, Vol. XXXIII, p. 374. 



PILOCARPINE ON THE CIRCULATORY SYSTEM 



125 



enced by pilocarpine. This is due undoubtedly to the fact that these 
organs do not have a well-developed nervous controlling mechanism. 
Any influence which is exerted on the two organs is probably due, 
therefore, to indirect effects through the vascular system. Pilocarpine 
influences the flow of blood through the glands, and this, together with 
the increased production of sugar by the liver, would account for the 
observed increase in sugar in pilocarpine milk. 

2. Pilocarpine on the circulatory apparatus. — Pilocarpine in- 
jected intravenously leads to a marked fall of blood-pressure. The 
fall is secondary to a marked inhibition of the rate of the heart. 

/ 3. The heart. — Pilocarpine leads to slowing of the heart in both 
the frog and the mammal. This may reach a complete inhibition 








Fig. 32. — Showing the increased sensitiveness of the vagus control in the cat 
after administration of 0.1 milligram of pilocarpine. The right vagus was cut, periph- 
eral end stimulated, the induction coil at 25 cm. showed no inhibition, at 20 cm. 
marked inhibition before the drug was applied. A, right vagus stimulated 23 cm. 
normal ; B, same stimulation after pilocarpine ; C, stimulation at 25 cm., after pilocar- 
pine. The increased sensitiveness of the vagus gradually wore off. a, pressure base 
line ; 6, time in seconds ; d, duration of stimulus ; e, Hurthle's manometer record. The 
top tracing shows the blood-pressure. From Marshall. 

as the action of the drug proceeds. /The cardiac slowing is due to 
a stimulation of the vagus terminations, since it occurs after section 
of the vagi ; in fact, after paralysis of the vagal ganglia) Marshall x 
has shown that small doses of pilocarpine at once depress, then 
quickly increase the response of the vagus to stimulation. The 
reaction is an additive one, since the drug and the electrical stimula- 
tion produce the same end effect on the cardiac apparatus. 

Pilocarpine, curiously enough, when taken by the mouth is asso- 
ciated with an increase in the pulse rate noted quite constantly in 
1 Marshall, C. R. : Journal of Physiology, 1904, Vol. XXXI, p. 150. 



126 PILOCARPINE, MUSCARINE, PHYSOSTIGMINE 

man. This has been variously explained. By some it is considered 
as a direct stimulation of the cardiac accelerator endings. But others, 
notably Marshall, consider it a secondary effect. This latter is prob- 
ably the safer explanation. 

[Pilocarpine and atropine are antagonistic in their cardiac effects, 
though the former is only about one-twentieth as vigorous in its 
toxic action. 1 

4. The blood-vessels. — Pilocarpine has little effect on the blood- 
vessel mechanism in comparison with its more profound glandular 
action. Given intravenously, the marked fall of blood-pressure sug- 
gests vasomotor paralysis. The pressure change, however, is chiefly 
due to cardiac slowing at this stage. There is some slight vasomotor 
action, but not enough to overcome the cardiac slowing. Perfusion 
of isolated organs (Dixon) shows vasoconstriction. The later and 
more toxic action leads to paralysis of the vasomotor center. 

5. Pilocarpine on the respiratory tract. — In addition to its 
nerve effects, pilocarpine produces a contraction of the bronchial 
musculature, which tends to interfere with the free respiratory move- 
ments, making them more or less labored. In this instance, as in 
many pharmacological situations, a chain of secondary influences 
supervenes. The great increase in the secretions of the respiratory 
passages produces an increase of mucus, etc., that tends to block 
the smaller tubes interfering profoundly with the respiratory inter- 
change. 

Studies indicate that the total respiratory exchange, especially 
the output of carbon dioxide, is increased under the influence of pilo- 
carpine. This is to be expected because of the great increase in 
functional activity of glandular and other motor tissues. 

6. On the central nervous system. — At first pilocarpine is slightly 
stimulative to the nerve centers of the medulla and cord. After larger 
doses there is a tendency to paralysis and collapse, especially of the 
medullary centers. The respiratory center is markedly depressed by 
pilocarpine. The rate is greatly slowed and the amplitude of the 
respiratory excursions diminished. The slight initial stimulation of 
the vasomotor center is followed by paralysis. 

7. Pilocarpine on the alimentary tract. — Pilocarpine produces a 
marked, in fact violent, increase in the peristalses of the stomach 
and intestine. It stimulates at the point of union of the motor 
nerves and smooth muscle cells, picking out the motor mechanism 
apparently to the exclusion of the inhibitory mechanism. This action 
is easily demonstrated by rings of muscle from the stomach of a cold- 



ACTION OF PILOCARPINE ON THE EYE 



127 



blooded animal. It is expressed also in the griping muscular con- 
tractions with pain and by the occasional purging and vomiting noted 
after the excessive administration of pilocarpine. 

8. Action of pilocarpine on the iris and the ciliary mechanism 
of the eye. — The constriction of the pupil is an obvious and easily 




Fig. 33. — Influence of pilocarpine on the bronchial muscles, and on the blood- 
pressure. Trimethylamin hydrochloride produced the opposite result. The further 
details of the experiment are explained on the figure. From Jackson. 

noted result associated with the symptoms of pilocarpine action. The 
accommodating mechanism is also stimulated to contraction. Refer- 
ence to the discussion of the action of atropine, also of epinephrine, 
whore a review is given of the normal physiological mechanism of 
the eye, will show that the contraction of the pupil depends upon a 
stimulating action of either some portion of the oculo-motor nerve 
or of the smooth muscle of the iris itself. Anderson * has especially 

1 Anderson, H. K.: Journal of Physiology, Vol. XXXIII., p. 414, 1905. 



128 PILOCARPINE, MUSCARINE, PHYSOSTIGMINE 

investigated the problem. By a series of exclusion experiments he 
has shown that pilocarpine produces an even stronger contraction 
of the iris after section of the oculo-motor nerve, as it does also after 
removal of the ciliary ganglia. In this last case the contraction is 
more prolonged than when the oculo-motor nerves are intact. One 
hundred and nineteen days after removal of the ganglia, when 
the short ciliary nerves are presumed to be degenerated, pilocarpine 
still produces contractions of the constrictor muscles of the iris. He 
came to the conclusion that pilocarpine can act on the sphincter 
muscle itself. It is admitted, however, on the basis of greater re- 
sponse with intact nerves, that pilocarpine acts also at the point of 
nerve endings. The accommodative spasm is explained in light of 
these experiments as a peripheral muscle and motor-nerve stimulating 
effect of pilocarpine. 

IV. 

Condensed Summary of the Pharmacological Action of Pilocarpine. 

Pilocarpine and related alkaloids lead to marked stimulation 
of the peripheral motor structures. There is a striking increase in 
the amount of perspiration, saliva and other secretions of the 
alimentary and respiratory tracts. Pilocarpine has no direct physio- 
logical action on the mammary gland or on the kidney, but it in- 
creases the glycogenic functions of the liver. The nervous mus- 
cular mechanisms of the eye are sharply stimulated through action 
on the nerve terminations and on the constrictor muscle itself. 
The heart is slowed by an initial stimulation of the inhibitory 
mechanism at its terminations, an effect which is followed by final 
paralysis. In therapeutic doses medullary centers are slightly stimu- 
lated, in large doses paralyzed. The paralysis is most marked on the 
respiratory center and on the vasomotor center. In toxic doses heart 
muscle is weakened and the circulation depressed, the respiration 
is shallow, and edemic obstruction may take place in the lungs. 

Pilocarpine is antagonized by atropine, which is an antidote. 

II. MUSCARINE. 

I. 

Historical and Chemical. 

Muscarine is a very toxic alkaloid present in the poisonous mush- 
room, Amanita muscarius. Schmiedeberg has produced an artificial 



OUTLINE OF PHARMACOLOGICAL ACTION 129 

muscarine by the oxidation of choline, to which it is closely related, 
having the formula C 5 H 14 N0 3 . The chemical relationship between 
choline and muscarine is shown by the following structural formulae : 



CH 3 CH 3 CH 2 OH 
CH 3 — N 


CH 3 CH 2 CH 2 
CH 3 — N 


CIV OH 


CH 3 ' 


Choline 


Muscarine 



II. 

Outline of Pharmacological Action. 

The action of muscarine is very similar to that of pilocarpine, 
though it is more strongly stimulative of parenchymal tissues. Its 
general effects are : 

1. A marked slowing of the heart by stimulation of vagus terminal 
endings. 

2. Accommodation spasm, with constriction of the pupil of the 
eye. 

3. A marked increase in gastric and intestinal peristalses. 

III. 
Details of Pharmacological Action. 

i. Muscarine on the heart and circulatory system. — The 
typical action of muscarine is illustrated by its influence on the heart. 
"When muscarine is perfused through the frog heart or painted over 
the whole heart a marked slowing leading to complete standstill 
quickly ensues. The muscarine effect is not due to a paralysis of the 
contractile substance, since at any time direct stimulation of the 
ventricle of the heart leads to a contraction. The muscle tissue is 
irritable and contractile, but held in inhibition. This picture is 
further emphasized by the immediate recovery of contractions after 
painting the heart with atropine. The pause disappears and a per- 
fectly normal rhythm ensues. It is evident that atropine and mus- 
carine act upon the same structures, namely, the terminal fibers of 
the vagus in the heart tissue. 

In certain animals, especially invertebrates which have well-de- 
veloped cardiac nerves, there is a specific stimulation of the accelerator 
mechanism, in a way comparable to the stimulation of the inhibitory 
mechanism in most mammals. Muscarine is without marked effect 



130 PILOCARPINE, MUSCARINE, PHYSOSTIGMINE 

on cardiac tissue as such, hence does not influence the embryonic 
heart before the nervous connections are established. However, there 
is a slight direct effect on isolated ventricular muscle of the terrapin, 
a general increase in the amplitude of the contraction with a some- 
what slower rate. 

2. On blood-pressure. — The administration of muscarine leads 
to an enormous fall of blood-pressure, but these results are almost 
exclusively due to the cardiac inhibition as previously described. 
Upon the intravenous injection of muscarine there is as complete a 
cessation of heartbeat in the mammal as results from effective vagus 
stimulation. This action can be controlled by graded doses almost as 
completely as the vagus itself. This inhibition is removed by counter 
injection of atropine, under the antagonistic action of which the 
blood-pressure recovers. 

3. Muscarine on the glands and on the alimentary tract. — 
Muscarine produces an increase in the secretion of salivary and other 
glands of the mouth and alimentary tract by a stimulation of the 
terminal secretory fibers at the same point acted upon by pilocarpine 
and apparently in the same way. 

In a similar manner there is a marked increase in the peristalses 
of the stomach ; in fact, of the entire intestinal tract. A 0.5-milligram 
dose of muscarine per kilo-given to a cat or dog is sufficient to pro- 
duce violent secretion of the salivary glands, and intense contractions 
of the stomach and intestine, with vomiting and purging. 

4. On the eye. — Muscarine produces a constriction of the pupil 
and contraction of the muscles of the accommodating mechanism of 
the eye. These results are accomplished through stimulation of the 
endings of the oculo-motor nerve on the muscle fibers involved. The 
stimulation of the terminal fibers of the oculo-motor is more pro- 
longed and enduring with muscarine than with pilocarpine, the 
toxic action of the latter tending to paralyze the mechanism. 

III. PHYSOSTIGMINE, OR ESERINE. 

I. 

Historical and Chemical. 

Physostigmine is derived from the seeds of the Calabar bean, 
Physostigma venosum, of the western portion of Africa. It has the 
chemical formula, C 15 H 21 N 3 2 . It was first isolated in 1864 by Jobst 
and Hesse. 



OUTLINE OF PHARMACOLOGICAL ACTION 131 

II. 

Outline of Pharmacological Action. 

Physostigmine, like pilocarpine and muscarine, produces a pro- 
found stimulation of terminal nerve fibers, but with greater effect 
on the parenchymal tissue itself. 

1. Marked constriction of the pupil and accommodative spasm 
of the ciliary muscles of the eye. 

2. A powerful stimulation of the muscular mechanism of the 
stomach, intestine, and the muscles of the urino-genital apparatus. 

3. A stimulation of the cardiac inhibitory apparatus. 

4. Initial slight stimulation, with deep depression of the function 
of the medullary centers, and to some extent of those of the spinal 
cord. 

III. 

Details of Pharmacological Action. 

i. Physostigmine on the eye. — The local ocular effects of physo- 
stigmine are demonstrated by dropping a one per cent, solution 
over the surface of the eye. After 20 to 30 minutes the pupil becomes 
constricted and the ciliary muscles sharply contracted, and the eye 
accommodated for near vision. This accommodative spasm lasts for 
several hours, three or more. The explanation of the physostigmine 
action is based on the view that the terminal fibers of the oculo-motor 
are sharply stimulated. If one stimulates the cervical sympathetic 
in the neck there occurs the normal complete dilation of the pupil, 
showing that this apparatus is not involved, i.e., not paralyzed by the 
action of the alkaloid. That the action is on the terminal fibers is 
shown by the fact that constriction takes place after operation, cut- 
ting the short ciliary nerves or removal of the ciliary ganglia. If 
degeneration of these peripheral fibers is allowed to take place, then 
the eserine effect is less marked or lost. It was formerly thought that 
physostigmine produced a direct stimulation of the muscles them- 
selves. 

Anderson, who has performed degeneration experiments on nu- 
merous animals, finds that physostigmine is not active on the iris 
after the peripheral nerves have degenerated. Acceptance of this 
observation tends to throw doubt on the current view that physostig- 
mine stimulates smooth muscle in numerous other organs. He finds 
that physostigmine contractions return early in the regeneration of 



132 PILOCARPINE, MUSCARINE, PHYSOSTIGMINE 

these fibers, even before they become sensitive to electrical stimulation. 
All these facts point to localization of the action on the endings of the 
oculo-motor nerve. Heine has demonstrated by histological methods 
that the ciliary muscles of the eye and the muscles of the iris are 
actually contracted in eserine poisoning. 

Physostigmine also contracts the striated muscles of the bird's eye, 
differing in this respect from the action of atropine, which does not 
paralyze striated nerve endings. 

2. Physostigmine on the circulatory apparatus. — Intravenous 
administration of physostigmine produces an immediate fall of blood- 
pressure. If the dose be toxic the picture is similar to that upon the 
maximal stimulation of the vagus nerve. In the therapeutic dose 
there is a marked slowing of the heartbeat associated with inter- 
mediate periods of more complete cardiac inhibition. This effect is 
to be explained on the ground of marked vagus stimulation for the 
whole heart. Atropine removes the depressing action of physostigmine 
by counteracting its effect on the nerve endings. It would seem that 
little or no central stimulation occurs on those nervous centers regu- 
lating the circulatory apparatus. Carlson, however, has shown that 
the extra-cardiac ganglia of limulus are stimulated by relatively 
strong solutions of physostigmine. 

The isolated vertebrate heart or the heart tested in situ always 
shows a pronounced slowing upon the administration or application 
of physostigmine. The physiological analysis of the results proves 
that this action is primarily due to pronounced stimulation of the 
terminal vagus fibers as in muscarine poisoning. There is this differ- 
erence, namely, that atropine does not completely eliminate the 
eserine. Experiments on isolated strips of terrapin heart reveal the 
reason of this failure of complete atropine antagonism. Strips sub- 
jected to physostigmine solutions, .01 to .02 per cent, in physiological 
saline, show a slight slowing with a pronounced increase in the ampli- 
tude of contraction. The increase of amplitude is interpreted to 
mean a direct muscular stimulation. The slowing is not so easily ex- 
plained. One may assume that the terminal inhibitory fibers in 
this isolated muscle are stimulated somewhat slowing the rate, but the 
stimulation is not pronounced enough to overcome the direct effect on 
the amplitude of the contractions. This we have checked on strips 
from tested atropinized hearts and find that now the increase in 
amplitude of contractions is greater and that the rate is often, though 
not always accelerated. 

3. Physostigmine on striped muscle. — Physostigmine differs from 



DETAILS OF PHARMACOLOGICAL ACTION 133 

other members of this series in that it stimulates skeletal muscle. The 
effect of the drug apparently falls both on the motor end plates and 
on the striated muscle substance. The former deduction is proven by 
the fact that sub-minimal stimuli for normal motor nerves become 
effective after the administration of physostigmine. 

Physostigmine will increase the irritability of the motor end plate 
sufficiently to overcome or antagonize the less profound paralyses 
produced by curare. Pal has shown that a curarized animal, in which 
the voluntary muscles were no longer active to nerve stimulation, 
will recover the motor control after intravenous injection of physo- 
stigmine. He considers physostigmine a true antagonist and antidote 
to curare. Skeletal muscle is set into fibrillar contraction by stronger 
solutions of physostigmine. 

4. Physostigmine on the muscles of the stomach and intestines. 
— The peristalsis of the stomach is markedly increased by physostig- 
mine in a manner similar to that of pilocarpine and muscarine. In- 
testinal peristalsis is also increased. These effects are accomplished 
through stimulation of the terminations of the vagus nerve, i.e., the 
terminal neurone in the vagus path. Eserine produces more pro- 
nounced contraction in these organs because it also directly stimu- 
lates the unstriped muscle. The gall bladder and its sphincter 
strongly contract. In fact, all organs possessing the unstriped muscle 
are set into a greater or less degree of contraction by eserine. The 
spleen, the urino-genital apparatus, including the uterus, and the 
muscles of the small arteries are all involved. 

Atropine is only partially antagonistic to this physostigmine effect. 
It does not eliminate the direct muscular action, only antagonizing 
that factor due to the stimulation of the nerve ends, but not counter- 
acting the blood-vessel effects nor the striated muscle stimulations. 

5. On the central nervous system. — The influence of physostig- 
mine on the medullary centers controlling the circulation is wholly 
insignificant, but the action of physostigmine on the respiratory 
center is of special importance. Therapeutic doses have been de- 
scribed as leading to initial acceleration of respiration, though in 
laboratory experiments on mammals this acceleration is slight and 
quickly passes into a slow respiratory rate with diminished amplitude 
and final complete inhibition. The respiratory pause is not due to 
the interference with the motor nerve endings, since, as has already 
been stated, these are stimulated. Section of the vagus nerve does 
not eliminate the effect, hence we must assume that the toxic influence 
is on the respiratory center itself. If, in a mammal during physostig- 



134 PILOCARPINE, MUSCARINE, PHYSOSTIGMINE 

mine respiratory pause, atropine be injected intravenously, there is 
ultimate respiratory recovery. The first influence of the atropine is 
of course to release the heart from the vagus control, which mechanism 
is under stimulation by physostigmine. Then, after a variable in- 
terval, amounting in one published illustration x to 30 seconds, there 
is a slow, gradual recovery of respiratory rate and amplitude. One 
must explain this striking antagonism of atropine for physostigmine 
as due to the fact that atropine is much more profoundly stimulative 
in its primary action on the respiratory center. The toxic stage of 
both drugs leads to paralysis of this nervous mechanism. A toxic 
dose of physostigmine is small and produces cessation of respiratory 
movements long before elimination of function of the circulatory 
apparatus. In ordinary toxic doses the cause of death is respiratory 
failure with asphyxiation. 



IV. 

Condensed Summary of Action. 

Physostigmine has a pronounced stimulating effect on practically 
all motor nerve terminations — the salivary glands, gastric glands, 
lachrymal glands ; the muscular apparatus of the eye, of the stomach 
and intestine, of the bladder and uterus, and of the bronchial tubes. 
It stimulates the nerve terminations in skeletal motor nerves, antag- 
onizing curare. Eserine also stimulates practically all the active 
parenchymatous tissues, such as the glands, the heart muscle, skeletal 
muscle, and all smooth muscle tissues, with the exception of those of 
the eye. It has an ultimate paralytic effect on the nerve centers of 
the medulla the respiratory center being especially sensitive. The 
action of physostigmine is antagonized by atropine on all nerve struc- 
tures which are primarily stimulated by physostigmine, but its ter- 
minal action on the peripheral tissues is not so antagonized. 

1 Greene, Chas. W. : Experimental Pharmacology, p. 46, Fig. 2. Philadelphia, 
1909. 



CONDENSED SUMMARY OF ACTION 
COMPARISON OF THE PILOCARPINE GROUP. 



135 





Central 
nervous 
system 


Nerve end- 
ings in 
glands 


Nerve end- 
ings in 
smooth 
muscle. 


Cardiac 

vagus 

endings. 


Skeletal 
muscle 
endings. 


Direct action 

on terminal 

tissues. 


Pilocarpine. 


Depressing to 
axial nerve 
centers. 


Violently 
stimulates in 
all glands ex- 
cept kidney 
and mam- 
mary. 


Stimulates 
alimentary, 
urino- genital 
system, and 
eye. 


Stimulates. 


No effect. 


Slight but 
questionable. 


Physostigmine. 


Slight initial 
stimulation 
and early and 
profound pa- 
ralysisof axial 
centers. 


Stimulates. 


Violently 

stimulates all 
structures. 


Strongly stim- 
ulates. 


Stimulates. 


Stimulates 
but question- 
able as to the 
eye. 


Muscarine. 


Sti mulation 
followed by 
depression. 


Stimulates. 


Vigorous 
stimulation. 


Violent stim- 
ulation. 


Paralysis. 


Little or none. 


Atropine. 


Vigorous 
stimulation 
and toxic pa- 
ralysis. 


Simple paral- 
ysis. 


Paralysis. 


Paralysis, ex- 
cept blood- 
vessels and 
inhibitory 
nerves of ali- 
mentary ca- 
nal. 


No effect. 


No effect. 



CHAPTER XIV. 
THE NICOTINE SEEIES. 

I. 

Historical and Chemical. 

Tobacco, Nicotiana tabaeum, possesses an alkaloid, which has 
certain characteristic influences on the reactions of the body, to 
which the widespread use of tobacco is to be attributed. Tobacco was 
introduced into general use among Europeans following the dis- 
covery of America. Lord Raleigh, who was impressed by the Indian 
custom, brought home tobacco and taught the English court the 
Indian method of smoking it. At the present time the use of tobacco 
is widespread, and is chiefly limited to smoking and chewing. The 
latter method results in the swallowing of small quantities of the 
juices of tobacco with the saliva, while the former results in absorp- 
tion of nicotine and related chemical derivatives from the smoke 
inhaled. 

Chemically nicotine is a pyridine of the following structural 
formula as given by Schmiedeberg : 

CH KCH 3 

/\ /\ 

HC C HC CH 2 

HC CH H 2 C CH 2 

When heated, as in cigar smoking, the nicotine is partially broken 
down, forming pyridine and pyridine compounds. 

Lobelia inflata possesses an alkaloid, lobeline, with the chemical 
formula, C 18 H 23 N0 2 , which has a physiological action similar to that 
of nicotine. Duboisia Hopwoodii possesses an alkaloid, piturine, 
C 12 H 16 N 2 . This alkaloid has effects identical with nicotine, according 
to Langley and Dickinson. 

The water hemlock, Conium maculatum, contains a series of alka- 
loids, which have reactions in the body somewhat similar to nicotine. 
Of these coniine is the most important. 

136 



OUTLINE OF PHARMACOLOGICAL ACTION 137 

II. 
Outline of Pharmacological Action. 

1. Nicotine produces a primary out mild stimulation of the 
nervous system at all points, followed by a marked depression. 

2. It is specific in its action upon the pre-ganglionic synapses of 
the autonomic system, at first mildly stimulating, but later producing 
a profound and prolonged paralysis. 

3. Cardiac muscular tissue is at first strongly stimulated, then 
later depressed. Other muscular tissues, the smooth muscle, and 
skeletal muscle, are similarly though less strongly affected. 

III. 

Details of Pharmacological Symptoms. 

Nicotine is a drug which is strikingly disturbing to the normal 
functions of the body. When it is used for the first time and in 
semi-toxic amount the symptoms indicate a profound general stimu- 
lation of all parts of the body. There is increased respiration, a 
general rise of blood-pressure, vasomotor constriction, a slow heart 
in the incipient stage, but a rapid and irregular heart in the advanced 
stage. There is nausea with vomiting, very often accompanied by 
increased peristalsis of the alimentary tract and purging. Excessive 
doses may cause death, which is produced through paralysis of the 
respiratory muscles and of the central nervous system. 

i. On the central nervous system. — Nicotine stimulates the en- 
tire central nervous system, apparently more strongly from above 
downward. This stimulation is slight and transient, giving way to a 
depressed or sedative condition. 

2. On the cerebral cortex and medulla. — Beneficial action of 
nicotine on the cortex has not been demonstrated in so far as the 
ability to do psychic work is concerned. Under conditions of mental 
disturbance and hyperirritability nicotine is said to contribute to a 
feeling of comfort and quiet, i.e., is soothing to an overwrought 
nervous mechanism. This effect is undoubtedly an expression of 
the second stage in the responses of the body to the alkaloid. 

On the basal centers of the nervous system, especially of the 
medulla, the initial stimulating action of nicotine is more pronounced. 
This is shown partly through the great automatic regulative centers 
controlling the action of respiration, the circulation, the alimentary, 



138 THE NICOTINE SERIES 

and glandular systems. The respiratory center is stimulated to an 
increased respiratory rhythm and amplitude. In the more advanced 
stages this effect gives way to one of depression. The cardiac regula- 
tive centers, both inhibitory and accelerator, are likewise rendered 
more sensitive. This leads to a slowing of the heart through the 
central stimulation, since the inhibitory mechanism is preponderant. 
After the action of nicotine becomes more intense, the accelerator 
mechanism is more profoundly stimulated, hence there will be periods 
of cardiac acceleration approaching palpitation. The vasomotor cen 7 
ter is at first sharply stimulated, leading to a marked peripheral con- 
striction of the arterioles. Later this gives way to vasomotor paraly- 
sis. The medullary nerve centers controlling the sweat glands of 
the skin, the salivary glands, also probably the gastric and pancreatic 
glands, are at first stimulated, then later depressed. 

3. The spinal cord. — The nervous mechanisms of the spinal cord 
are not so profoundly involved as those of the medulla. However, 
the reflex centers of the cord are rendered more sensitive to the 
ordinary inflow of stimuli, hence give more profound discharges 
than normal. This condition is quickly followed by one of obvious 
depression, which in the toxic stage may result in motor paralysis. 

4. Nicotine action on the peripheral ganglia. — The specific ac- 
tion of nicotine falls not upon the central nervous axis, but upon the 
peripheral ganglia of the autonomic nervous system. Here, too, nico- 
tine produces a passing stimulation, but followed by a marked and 
quick depression, with complete elimination of function. This specific 
action takes place at the union between the pre- and post-ganglionic 
neurones. 

Schmiedeberg was the first to properly locate the characteristic 
specific action of nicotine, proving the same by its influence on the car- 
diac inhibitory mechanism. He showed by a skillful series of experi- 
ments that the elimination of the vagus control over the heart was due 
to the loss of function in the cardiac ganglia. The stimulation of the 
vagus nerves in the neck failed to produce an inhibition of the heart 
at a time when stimulation of the ganglia of the heart at the sinus 
produced inhibition. It was evident that such an experimental result 
could only be obtained by a block of the nerve impulse in the cardiac 
ganglia. 

This point of specific action of nicotine has been proven through 
later work to be general for all the autonomic mechanisms. Langley 
and his pupils have demonstrated this general law, and by turning 
the fact about and using it as a means of interpretation, have been 



ON THE CIRCULATORY SYSTEM 139 

able to very greatly widen our physiological knowledge of the whole 
nerve complex of the so-called sympathetic system. The changes of 
function produced by nicotine on the various special motor organs 
are largely dependent upon the action of nicotine on the peripheral 
sympathetic ganglia. The usual delicate and well-balanced normal 
physiological responses become blunted or impossible when the nerve 




Fig. 34. — Effects of nicotine on the contractions of the isolated sinus-auricle strip, 
terrapin. Between the arrows the preparation was bathed in .01 per cent, nicotine. A 
70 second interval between the two parts of the record. Note both the tonic and the 
fundamental contractions are strongly stimulated, the tonic contractions at the begin- 
ning- of the nicotine action, the fundamental contractions throughout. Time in seconds 
New tracing by Williams. 

control is eliminated by the nicotine blocking of nerve paths through 
the peripheral ganglia. 

5. The action of nicotine on the circulatory system. — A physio- 
logical mechanism so complicated as the circulatory apparatus must 
of necessity be profoundly influenced by a drug which has widely dis- 
tributed reactions in the human body. So it is with nicotine. This 
alkaloid causes marked changes at least at four fundamental points 
in the circulatory apparatus, namely, on the cardiac muscle itself, the 
heart's local nervous mechanisms, the medullary centers for the 
heart, and on the vasomotor nervous complex. The resultant activity 
of the circulatory complex produced by nicotine shows itself of course 
in changes in the blood-pressure, and pulse rate and pressure. A 
very weak dose of nicotine produces a rise of blood-pressure. If the 
nicotine action becomes stronger, as with a medium dose, this pressure 
remains up ; in fact, continues to rise. Only in the toxic stage does 
the pressure fall and finally become nil at death. The components 
entering into and producing this rise of pressure are discussed more 
fully below, but the condensed statement is shown in the following 
table : 



140 THE NICOTINE SERIES 

ACTION OF NICOTINE ON THE CIRCULATION. 



Blood-pressure 

Heart rate 

Heart amplitude . . 

Vagus control 

Accelerator control. 
Vasomotors 



Dose. 



Weak. 



rise 
slow 

increased 
j strongly ) 
( increased f 

increased 

increased 



Medium. 



rapid 

greater 
decreased 

and lost 
increased 

decreased 



Toxic. 



fall 

slow and 

failing 

less 



decreased 

and lost 

lost 



6. The action of nicotine on cardiac muscle. — Cardiac muscle re- 
sponds very sharply to the presence of nicotine, both by a change 
of rate and of amplitude, i.e., force of the contraction. Both these 
factors are increased under the stimulating action of therapeutic 
quantities of nicotine. The point can be proven readily by studies 
on isolated strips of cardiac muscle and by the reactions of isolated 
hearts, both mammalian or warm-blooded and the various cold- 
blooded hearts. Strips of ventricular muscle, when surrounded by 
physiological saline containing approximately .001 to .002 per cent, 
of nicotine show an increase of amplitude amounting to from 10 to 
20 per cent, and an acceleration of the rate which is more or 
less variable. The perfused frog's heart shows comparable re- 
sults. 

The most striking illustration of this influence is found when the 
isolated mammalian heart is perfused with physiological solutions con- 
taining nicotine, as shown in Figure 35. Often the amplitude of 
the contractions of the heart is doubled and the rate strongly accele- 
rated. Undoubtedly a similar cardiac muscular effect is produced on 
the heart in its normal relations in the body. The late and relatively 
toxic actions of nicotine are depressant for cardiac muscle. This 
factor appears in the after effects in those experiments in which there 
is a maximum of primary stimulation. 

7. The local nervous apparatus of the heart. — The peripheral 
nervous reactions to nicotine are best demonstrated by perfusions 
either on isolated organs or in blood-pressure studies. If one follows 
Schmiedeberg's technique, the results of which have already been 
given, he will note that the heart is at first slightly slowed for a 
few minutes, probably due to the local stimulation of the nerve 



THE NERVES OF THE HEART 141 

cells of the cardiac ganglia. This stage, however, quickly passes. If 
now the vagus nerve, or the vago-sympathetic of the frog be stimu- 
lated in the neck, there is no longer an inhibition of the heart. In 
the frog, in fact, there is generally an acceleration. Direct stimulation 
of the sinus still produces inhibition, the observational fact on which 
Schmiedeberg reached his deduction that the pre-ganglionic nerve 
endings are blocked in the sinus ganglia. The fact that the ganglionic 
endings of the accelerator nerves in the frog are located central to 




Fig. 35 — Nicotine. 0.0002 per cent, in blood-Ringer's solution, on the isolated heart 
of the cat. Temperature and perfusion fluid constant. A later experiment with .0005 
per cent, showed a more pronounced increase in the amplitude followed by a stage of 
depression from which recovery was very gradual. Rate before profusion 56, imme- 
diately after, 84. New tracing by Boutwell and Peeler. 

the point stimulated explains the acceleration observed in that 
animal. If one would dissect back of the stellate ganglion, in the 
frog to the white ramus from the third spinal nerve and apply an 
electrical stimulus, the acceleration observed on stimulation of the 
vago-sympathetic trunk will not occur. The nicotine has evidently 
poisoned the pre-ganglionic endings in the accelerator path just as 
effectively as in the inhibitory path. 

Emphasis has just been laid on the systemic effects that come from 
elimination of the coordinative nervous mechanisms. No better organ 
could be used in presenting the detrimental effects of the toxic alka- 
loids than this one of the action of nicotine on the cardiac regulative 
nerves. Certainly the coordinative control of the heart is one of 
the most fundamental factors in normal physiology. The elimination 
of this control, therefore, is obviously profoundly injurious. 

8. The vasomotor system. — Notwithstanding the cardiac slowing 
observed, the blood-pressure generally rises when nicotine is injected 



142 THE NICOTINE SERIES 

intravenously. This rise of blood-pressure is in no small part to be 
attributed to an increased tone of the peripheral blood-vessels. The 
central effects have already been mentioned, but there are also un- 
doubtedly peripheral actions, since vasoconstrictions occur in organs 
isolated from the central nervous system. Occasionally there is some 
vasodilation, instead of vasoconstriction, suggestive of stimulation of 
the vasodilator mechanism. 

When the tonic action from the cardiac inhibitory mechanism is 
eliminated, the blood-pressure may rise quite decidedly, largely from 
persistent vascular contractions. The blood-vessels dilate in the 
toxic stage. 

9. On the glandular apparatus. — The peripheral glands show an 
increased secretion upon the administration of nicotine. This is 
due to the central action of the drug on the medullary nervous mech- 
anism. In the larger doses the peripheral ganglia are specifically 
poisoned and the reflex secretion correspondingly suppressed. 
It is not clear to what extent nicotine acts on the gland tissue 
as such. 

10. The action of nicotine on the eye. — Nicotine paralyzes the 
nervous mechanisms of the eye. In fact, one of the simplest methods 
of demonstrating the specific nerve action of nicotine in laboratory 
use for many years, thanks to the researches of Langley, is that of 
bathing the cervical nerve and the superior cervical ganglion with 
0.5 per cent, nicotine. Bathing the nerve trunk does not interfere with 
the passage of a nerve impulse. The function of this ganglion is 
blocked by the specific nicotine poisoning of the synapses and 
there is a failure of the usual dilation of the pupil upon cervical 
stimulation. 

The oculo-motor nerve has its pre-ganglionic unions in the ciliary 
ganglion. Nicotine poisons at this point too, hence tends to eliminate 
the conduction of the nerve whose function is to produce constriction 
of the pupil and an act of near accommodation, both processes vital 
to the adaptations of the eye to delicate vision. The diagrammatic 
relations of the nervous apparatus involved are illustrated in Figure 
26, under the chapter on atropine. The resultant general effects of 
nicotine vary somewhat in different animals, but in man there is usu- 
ally some degree of contraction of the pupil. 

11. Nicotine on the alimentary canal. — The complicated physio- 
logical control of the alimentary canal has been reviewed in some 
detail in the chapter on morphine. In order to understand the, 
action of nicotine one should keep in mind that complex interrelation 



THE NICOTINE HABIT 143 

of neurones involved in coordination of the function of the vagus 
motor fibers, the sympathetic inhibitory fibers, also the relationships 
of the plexuses of Meissner and Auerbach. Much of our informa- 
tion has been obtained by studies on isolated portions of the alimentary 
tract, especially the contributions of Magnus. 

Nicotine, in the general circulation, causes as one of its striking 
symptoms, violent peristalses of the alimentary canal. This symptom 
is noticed and often spoken of by the social users of tobacco. How- 
ever, it is a symptom which comes in the more pronounced stage of 
nicotine intoxication, i.e., upon the smoking of strong cigars. As 
a matter of fact, the very first and mildest influence of nicotine on 
the alimentary canal is a quieting or inhibitive phenomenon. This 
is due to the influence of the alkaloid on the sympathetic or inhibitive 
fibers, the incipient nerve stimulative stage that has been noted in 
several previous connections. This stage is soon passed over, being 
followed by specific toxic elimination of the sympathetic endings 
in the ganglia of the walls of the stomach and intestine. The elimina- 
tion of the pre-ganglionic neurones sets the Auerbach 's plexus of 
the alimentary canal free, which, according to Magnus, controls the 
local peristalses of the isolated organ. It is open to question, yet the 
probabilities are that nicotine acts as stimulative to the nerve cells 
of the plexus of Auerbach. The alternative to this view, however, 
would explain the increased peristaltic movements of isolated prepara- 
tions by a direct influence on the muscular tissue. Even large doses 
of nicotine do not paralyze the contractions of isolated portions of 
the intestine. Magnus found that if atropine was combined with 
nicotine, then paralysis occurred, a result which would tend to the 
view that the nicotine alone acted on the nervous rather than the 
muscular tissue. 

12. Excretion of nicotine. — Nicotine is largely excreted from the 
body through the kidney. However, there is a slight amount of excre- 
tion through general glands, such as the sweat glands, salivary 
glands, etc. Apparently there is some fixation and oxidation of 
nicotine by the tissues, though this is probably slight. 

IV. 

The Nicotine Habit. 

The social use of tobacco is one of the most widespread, of all 
drug habits, tobacco at the present time being used in smoking, chew- 
ing, and taken in powder form as snuff. It has little place in prac- 



144 THE NICOTINE SERIES 

tical therapeutics, yet from the standpoint of experimental phar- 
macology and of toxicology it is very important. 

It is very difficult to secure an accurate and scientific estimate of 
the effects on the body of the constant use of tobacco. A great deal has 
been written and said, some advocating strongly that no appreciable 
effects follow the social use of tobacco, others with an equal vehemence 
attributing extensive and profound disturbances to its presence. The 
scientific observations depend, for the most part, on acute experi- 
ments such as have been related in the preceding pages. Obviously 
a summary of these pages shows that the alkaloid nicotine either 
directly or indirectly produces variations in the function of prac- 
tically all parts of the body. Stated generally this variation is a 
mild incipient acceleration of functional activity followed by a gen- 
eral depression and toxicity in the more pronounced stages of its in- 
fluence. The picture is complicated by selective toxicity to the widely 
distributed autonomic mechanisms. One must assume that repeated 
use of the drug produces the same cycle of changes, though their 
relative intensity varies greatly in that the body only slowly regains 
its normal condition after it has once been subjected to nicotine. All 
succeeding doses, i.e., smokes, etc., proceed from a very much changed 
norm. Then, too, a marked tolerance is acquired by the body as 
an organism. 

A single use, say the first smoke of tobacco, will leave the body 
in a condition somewhat depressed below its normal average func- 
tional alertness. This depression falls upon the nervous system, both 
central and peripheral, on the heart, blood-vessels, glands, alimentary 
canal, and muscles. Repeated use is followed by similar, but more 
accentuated depression. This is just the foundation for that 
condition of general body sensation which drives an individual to 
continued use of any agent which runs the cycle of initial stimula- 
tion and after depression, typical of nicotine. These depressed 
sensations and general body feelings urge to repetition of the earlier 
experience. When the use of the drug is mild, what is generally 
considered as moderate, then the driving sensations are less vigorous. 
If the indulgence is extreme in any instance the disturbance of mental 
poise and well-being is correspondingly great. The individual takes 
tobacco, therefore, in order to produce and maintain that incipient 
stimulative stage. He is driven to continued repetition by the after 
depressions which characterize the action of tobacco in every form. 

Any stimulative agent acts like a whip to the physiological mech- 
anisms of the body. If those mechanisms be delicately poised and 



THE NICOTINE HABIT 145 

high strung, then the whip leads to nervousness and incoordination 
in the early phases of its action and to inevitable fatigue and exhaus- 
tion later. Repetition of the stimulus, in the long run, leads to an 
average physiological state which is far below the average normal 
for the individual before the use of the drug. One is led to suspect 
that herein lies the evil in the case. While there is no vital lesion 
resulting from the use of tobacco there is a diminution of the delicacy 




Fig. 36. — Blood-pressure in the decerebrate cat. The effects of the injection of 
liver extracts, A from a normal rabbit, B, from a nicotine tolerant rabbit. The extracts 
were made from equal parts of pulverized and dried liver, and each was incubated with 
0.01 gram of nicotine for two hours and thirty minutes. Time — 5 seconds. From 
Dixon and Lee. 

of sensibility, a reduction of physiological ability, a slight but general 
lowering of the energy and endurance of the body. 

Tolerance. — It is a well-known fact that individuals respond less 
strongly to successive doses of nicotine. "While the first cigar may pro- 
duce acute symptoms of nicotine poisoning the individual soon ac- 
quires the ability to smoke, not only one, but several without the 
extreme symptoms. Dixon and Lee 1 have lately attacked this prob- 
lem. By the method of repeated doses of nicotine, extending through 
several weeks' time, they were able to secure animals of marked 
tolerance. Proceeding on the theory that " nicotine tolerance is due 
to the destruction of the alkaloid by the tissues " they made liver 
extracts of tolerant animals with non-tolerants for controls. These 
extracts were each mixed with a definite quantity of nicotine, allowed 
to incubate for two and one-half hours, then were estimated for 
nicotine content by the physiological method of blood-pressure. 

Dixon and Lee say, ' ' These experiments show that a certain small 
degree of tolerance can be obtained to nicotine, and that this is brought 
about by the destruction of the alkaloid. The destruction goes on verjr 

1 Dixon, W. E., and Lee, W. E. : Quarterly Jour, of Experimental Physiology, 
Vol. V., pp. 373-383, 1912. 



146 



THE NICOTINE SERIES 



slowly, and it can never be accelerated to such a degree that an in- 
jection of a poisonous dose of nicotine into the circulation of an 
animal will lose any large amount of its effect. If the nicotine reaches 
the circulation slowly and in minute quantities it may be dealt with by 
the tissues, and this is the condition which we may assume obtains 
during tobacco smoking. ' ' These observations indicate that such nico- 
tine tolerance as is acquired depends upon the development of an 
oxidizing enzyme by the tolerant individual. 






CHAPTER XV. 

THE CONIINE, SPARTEINE GROUP. 

The alkaloids of this group form an intermediate series between 
nicotine on one hand and curare on the other. The most important 
members of the series are eoniine, lobeline, gelseminine, and sparteine. 
The most important member is eoniine, which may be taken as illustrate 
ing the actions of the other members. The chief difference is that of 
intensity and relative degree of toxic action. 

I. CONIINE. 
I. 

Historical and Chemical. 

The poisonous water hemlock, Conium maculatum, yields both from 
its roots and the stem the alkaloid eoniine, together with methyl 
eoniine, and conhydrine. Coniine is a piperidine compound and is 
interesting in that it was the first vegetable compound produced 
synthetically in the chemical laboratory, Hofmann in 1881. Methyl 
coniine differs from coniine by the substitution of methyl for the 
hydrogen attached to the nitrogen. Coniine has the chemical formula, 
C 8 H 17 N. The chemical relationships are indicated by the following 
formulae : 

Ha Ha Ha 

c c c c 

/\ /\ /\ /\ 

HC CH HaC CHa HaC CHa H 3 C CH a 

HC CH HaC CHa HaC CH-C 3 H 7 H 2 C CH-C 3 H 7 

Y V V V 

H H CH 3 

Pyridine Piperidine Coniine Methyl coniine 

II. 

Outline of Pharmacological Action. 

1. Coniine produces a very mild initial stimulation of the cen- 
tral nervous system, followed by pronounced depression and paralysis. 

147 



148 THE CONIINE, SPARTEINE GROUP 

2. It is toxic to peripheral nerve ganglia, acting similar to nicotine. 

3. Coniine is toxic to motor nerve endings of striated muscle, 
resembling curare. 

III. 
Details of Pharmacological Action. 

i. On the central nervous system. — Coniine, like nicotine, pro- 
duces some stimulation of the central nervous system, but this effect 
is so slight and the depressing action so strong that the stimulating 
factor becomes insignificant. The symptoms on man are characterized 
by depression. Following a therapeutic dose there is drowsiness, 
irregularity of respiration, unsteadiness of gait, slight dilation of the 
pupil, secretion of saliva with a tendency to nausea, and sometimes 
vomiting. 

In toxic dose coniine, especially in the impure form, is char- 
acterized by the production of a general paralysis, which involves the 
voluntary muscle system. The paralysis is progressive, ending finally 
in loss of respiratory movements. Schmiedeberg indicates that the 
toxic cycle is quickly passed and that death follows in from three 
to four hours. As an illustration of the toxic action we have Plato 's 
classical description of the death of Socrates under the administration 
of the poison cup, which, judging from the symptoms alone, has been 
attributed to the poison hemlock. 

2. On the autonomic nervous system. — Coniine, like nicotine, 
poisons the peripheral nerve ganglia. It is this which chiefly leads to 
disturbances of the normal physiological reactions of the peripheral 
tissue innervated through the autonomic system. There is some indi- 
cation of an initial stimulation of these ganglia, though this stage 
is very slight and evanescent. The main picture is that of tissue 
paralysis. However, it takes a larger dose of coniine to produce 
this poisonous effect than of nicotine, about in the ratio of 1 to 20. 

3. On the voluntary motor nerve endings. — Coniine has a par- 
alyzing effect on voluntary nerve endings, similar in kind to that of 
curare. 

When coniine is administered hypodermically to the frog the ani- 
mal soon loses its usual erect position, lies flat on the supporting sur- 
face with the legs more or less extended. It shows, in the toxic stages, 
some muscular twitching and irregular muscular reactions, which 
have some superficial resemblance to muscular cramps. However, 
this effect is primarily due to partial paralysis of the nerve endings 



CONIINE ON THE CIRCULATORY APPARATUS 149 

which eliminates the coordinative nervous control over the voluntary 
muscles. The presence of the muscular twitchings depends upon some 
central nervous change of an exciting nature, supposedly in the spinal 
cord. "When complete paralysis of the motor endings takes place 
the twitchings cease. Eespiration necessarily ceases, hence asphyxia- 
tion and death follow. 

4. On the circulatory apparatus. — The action of coniine on the 
circulatory apparatus is primarily due to its interference with the 
nervous mechanism. A transient rise of blood-pressure has been 
observed. This is attributable to a peripheral vasoconstriction, which 
is explained by some as of peripheral origin, possibly an expression 




Fig. 37. — Coniine on the contractions of ventricular muscle, terrapin. Between the 
points " on " and " off " the muscle was bathed with .006 per cent, coniine. Time in 
seconds. 

of the initial stimulation of peripheral ganglia in the vasomotor 
nerve mechanism. In the later stages the blood-vessels are dilated 
and the pressure falls. This is due to paralysis at the same points 
which receive the initial stimulation, i.e., the peripheral ganglia of 
the vasomotor nerves. This paralysis eliminates the tonic vasomotor 
action. 

The heart is little affected by coniine, in so far as the muscle is 
concerned, though its nervous mechanism is deranged. At first the 
heart beats somewhat slower from the initial stimulation of the 
vagus, but as paralysis of the cardiac ganglia quickly ensues the 
tonic vagus control is eliminated and acceleration occurs. In those 
lower animals, which have no vagus tone, this phenomenon is not 
observed. 

5. On the respiratory movements. — While the respiration under 
the influence of coniine shows some slight acceleration at first, the 
main picture is that of weakness and irregularity, the respiration 
becomes slow and the type of respiration shallow and irregular. In 
the toxic stage respiratory action is the first to disappear and death 
results from asphyxiation. 

Some difference of opinion exists in the literature as to whether 



150 THE CONIINE, SPARTEINE GROUP 

respiratory paralysis is primarily central or peripheral. The curare- 
like poisoning of the motor nerve endings is thought by many to be 
sufficient to account for the stopping of respiration. 

6. The excretion of coniine. — This alkaloid is excreted in the 
urine in part unchanged. Coniine rather readily breaks down and 
it is probable that a certain proportion of the drug may be decom- 
posed in the tissues. The excretion and decomposition is rapid, 
hence in coniine poisoning artificial respiration may ward off asphyxia- 
tion until recovery becomes possible. 

II. PYRIDINE AND PIPERIDINE. 

The action of pyridine and piperidine is similar to that of coniine, 
though very much weaker and less toxic. The chief action of the 
simpler compound, pyridine, is that of depression of the irritability 
of the nervous system. It shows little peripheral toxicity for the 
ganglionic cells. 

III. LOBELINE. 

Lobelia inflata yields an alkaloid, lobeline, C 18 H 23 N0 2 . Edmunds 
has described the action of lobeline as very similar, if not identical 
with that of nicotine. 

IV. GELSEMININE. 

Gelsemium sempervirens has yielded the alkaloids, gelsemine and 
gelseminine. The former alkaloid is described as producing strych- 
nine-like effects, especially on the frog. Gelseminine produces symp- 
toms very different from gelsemine and resembling the effects of 
coniine which have just been described. 

Gelseminine has a greater depressant action on the responses of 
the central nervous system than coniine. This influences the centers 
of the medulla and chiefly the respiratory center, thus leading to 
respiratory paralysis and death. 

Gelseminine, or some preparation of gelsemium, is employed rather 
widely to produce mydriasis. When drops are applied directly to 
the eye there is dilation of the pupil and loss of the power of ac- 
commodation. These phenomena are probably due in this case to 
paralysis of the nerve terminations in the muscles of the eye. 

On the heart gelseminine produces elimination of the function of 
the vagus, in this case by an early nicotine-like action on the cardiac 



SPARTEINE 151 

ganglia, Cushny, 1 and by a later atropine-like toxicity to the vagus 
terminations on the cardiac muscle. 

V. SPARTEINE. 

Sparteine is a liquid alkaloid, derived from the broom plant, 
Cytisus scoparius. 

Sparteine has a more toxic peripheral action and a less vigorous 
action on the central nervous system than other members of this 
series. In this regard it most closely resembles curare. Its fatal 
effects are due chiefly to the motor paralysis, especially of the nerves 
of the respiratory apparatus. 

On blood-pressure sparteine has a somewhat depressing effect. 
This influence is primarily due to the lowering of the vitality of the 
heart through toxicity on cardiac muscle, depression which is accen- 
tuated by a slight initial vagus stimulation. 

1 Cushny, Arthur R. : " Die wirksamen Bestandtheile des Gelsemium semper- 
virens," Arch. f. Path. u. Pharm., Vol. XXXI, pp. 49-68, 1893. 



CHAPTER XVI. 
EPINEPHRINE. 

I. 

Historical and Chemical. 

The internal secretion of the epinephros, epinephrine or adrenaline, 
possesses the formula, according to Aldrich, C 9 H 13 N0 3 . It is chemi- 
cally an amino alcohol with a pyrocatechin base as follows : 

HO |/\ CH.OH.CH 2 NH.CH 3 

HO I J 

This active material is elaborated in the animal body by the medulla 
of the suprarenal gland. That the suprarenal glands contain an active 
principle was first demonstrated by Oliver and Schaefer x in 1895. 
They worked with the extracts of the gland itself. Abel 2 was the 
first to isolate the active principle which he called epinephrine, and 
assigned the constitutional formula, C 10 H 11 NO 3 -iH 2 O. Takamine also 
isolated the active principle, calling it adrenaline, and perfected the 
methods for producing the material on a commercial basis. Folin has 
perfected a colorimetric chemical test for epinephrine accurate to 1 
in 3,000,000 parts. The test rests on a quantitative application of the 
blue color reaction between adrenaline and phosphotungstic acid, 
compared in a colorimeter against a standard color solution. Many 
other glands of the body produce a physiologically active principle, 
which is given off to the blood or lymph. But the type of reaction of 
adrenaline is closely approximated to that of certain of the plant alka- 
loids that have previously been described, in that its action is specifi- 
cally on the peripheral nerve endings. 

II. 

Outline of Pharmacological Action. 
1. Marked stimulation of sympathetic nerve endings of all types. 
The most striking of these groups are: 

1 Oliver and Schaefer: Journal of Physiology, Vol. XVIII., pp. 230-277, 1895. 

2 Abel, J. J.: Johns Hopkins Hosp. Bull., Vol. IX., p. 215, 1898; Vol. XII., 
p. 240, 1901. 

152 



DETAILS OF PHARMACOLOGICAL ACTION 153 

2. Vasoconstriction in most organs of the body, especially in the 
visceral regions. 

3. Acceleration of the heart and stimulation of accelerator end- 
ings, complicated by 

4. A secondary medullary stimulation of the vagus center. 

5. Stimulation of the sympathetic nerve endings of the salivary 
and lachrymal glands. 

6. Inhibition of physiological activities where the sympathetic 
furnishes inhibitory fibers, most pronounced in the gastric, intestinal, 
and uro-genital tracts. 

7. Dilation of the pupil. 

8. Glycosuria. 

III. 

Details of Pharmacological Action. 

1. Action on the nervous system. — Epinephrine is specific in its 
stimulative action on the terminal fibers of mechanisms of the sym- 
pathetic system in the various tissues. Hence the chief changes in the 
function of the body which are accomplished by this drug are those 
which involve reactions of the tissues controlled by the sympathetic 
nerves. 

There is some slight acceleration of reaction of the basic centers 
of the central nervous system, particularly of the centers of the 
medulla. Of these, the only ones of special importance are the 
respiratory and the cardiac inhibitory centers. The slowing of the 
heart observed on adrenaline injection is generally attributed to 
stimulation of the medullary inhibitory center. However, in experi- 
mental procedures in which the blood-pressure is prevented from 
rising above the normal, this slowing is slight or absent. This 
fact bears the interpretation that the slowing of the heart is a sec- 
ondary effect, produced by the increase in vagus tone, because of 
the marked general rise of blood-pressure. 

2. Epinephrine on blood-pressure — vasoconstriction. — The in- 
travenous injection of adrenaline into the circulation produces an 
enormous rise of blood-pressure, an effect first described by Oliver 
and Schaefer, who experimented with extracts of the gland itself 
several years prior to the chemical isolation of the active principle. 
"With maximal doses the blood-pressure may rise from 100 to 150 per 
cent. The blood-pressure remains high for a few moments, then slowly 
declines to approximately the original pressure. A characteristic of 
the picture is its short duration, Figure 42. 



154 EPINEPHRINE 

The tremendous rise of pressure is due to a marked arterial con- 
striction, which takes place, especially, in the visceral organs, such 
as the alimentary canal, spleen, kidney, also in the general systemic 
vessels. "When, for example, either the kidney or the intestine is 
placed in an oncometer and adrenaline injected into the circulation, 
the volume sharply decreases and the organ remains under its normal 
size, even at a time when the blood-pressure is at its maximum. 




Pig. 38. — Intravenous injection of 0.1 gram of suprarenal of the calf. Dog with 
the vagi cut ; the brachial plexus cut on the right side only. A, kidney volume ; B, 
volume of the right arm ; C, volume of the left arm ; D, carotid blood-pressure ; E, blood- 
pressure. The time of the injection as marked. From Oliver and Schaefer 

Meltzer 1 has shown that the duration of the vasoconstriction is 
dependent upon the maintenance of the normal relations of the sym- 
pathetic nerves. For example, if the cervical nerve of the rabbit is 
previously cut, then adrenaline produces a slower, longer, and 
stronger constriction in the blood-vessels than in the normal. This 
change takes place also after removal of the superior cervical s} T m- 
pathetic ganglion. 

The plethysmogram of the limbs (Oliver and Schaefer) may show 
a passive dilation, following the rise of the blood-pressure curve. 
However, when artificial means are taken to keep the general blood- 
pressure constant it is shown that the constrictions take place in 
the arterioles of the limbs also. This active constriction may be 
mechanically overcome, in ordinary experiments, as in Oliver and 
Schaefer 's tests, by the enormous general rise of blood-pressure. 

Studies on isolated organs show that perfusions of adrenaline 
solution produce vascular constriction. This, of course, indicates that 
the adrenaline effect is on the peripheral structures, but whether the 

1 Meltzer, S. J., and Meltzer, Clara: American Journal of Pht/siolog;/, Vol. IX., 
p. 147, 1903. 



DETAILS OF PHARMACOLOGICAL ACTION 155 

stimulation is due to a reaction on the vasomotor terminal fibers or 
a direct stimulation of the smooth muscle has been far more diffi- 
cult to determine. The classic work of Elliott, 1 and the later work 
of Dale, 2 have finally determined that adrenaline reacts >at the 
myo-neural junction leading to stimulative or inhibitive end reactions 
according to the particular autonomic nerve mechanism considered. 
Sollmann noted that isolated organs perfused, with adrenaline 




p IG< 39. — Shows the fall in hlood-pressure and the increase in the volume of the 
intestine upon injection of successive doses of 0.1 mgr. adrenaline. The vasoconstrictor 
nerve-endings have previously hern paralyzed hy 100 mgrs. chrysotoxin. Dale. 

solutions exhibited a constrictor effect followed by a late dilation. 
It is well known that certain visceral organs are doubly innervated, 
i.e., by antagonistic acting nerves. The above phenomenon is ex- 
plained on the ground that the adrenaline, not only stimulates the 
nerve endings of the constrictor mechanism, but at the same time 
the ends of the dilator fibers. Since vasoconstriction is the dominant 
nerve influence, the dilator effects come on only after the former 

1 Elliott, T. Pv.: Journal of /'////.s/o/o.r/.'/. Vol. XXXII., p. 401, W05. 

2 Dale, H. H.: Journal of Physiology, Vol. XXXIV., p. 163, 1006. 



156 



EPINEPHRINE 



have passed away. This phenomenon is rendered more intelligible 
when considered in connection with the well-known fact demonstrated 
by Bowditch and Warren that the vasodilator nerve mechanism retains 
its physiological properties longer after isolation from the central 
nervous system. 

Dixon x showed that adrenaline was inactive after the sympathetic 
endings were poisoned with apocodeine. Dale has given us the 
cleaner cut analysis by demonstrating that ergotoxine in larger doses 




Pig. 40.— Epinephrine 0.0012 per cent, in Ringer's solution perfused through the 
frog's heart. Normal rate, 30 ; maximum rate, 35. The amplitude was increased more 
than 100 per cent. New tracing by Summers. N 

produces a selective paralysis of the sympathetic stimulative mechan- 
isms without at the same time suppressing the function of the inhibi- 
tory mechanism. In his hands, adrenaline injected into the circu- 
latory system, after the poisoning of the vasomotor nerve endings by 
ergotoxine, produced a sharp stimulation of the vasodilator nerves. 
In fact, this was true of the inhibitory nerves of all organs, i.e., not 
only of blood-vessels but of the inhibitory nerves of the viscero-motor 
mechanism and of the uro-genital system, see table, page 159. In this 
clean-cut technique we have a means for the physiological separation 
of stimulative and inhibitory mechanisms, not only of the vascular 
system, but of other portions of the body as well. By the applica- 
tion of ergotoxine, it has been possible to demonstrate the fact that 

1 Dixon, W. E. : Journal of Physiology, Vol. XXX., p. 97, 1903. 



DETAILS OF PHARMACOLOGICAL ACTION 



157 



adrenaline stimulates both inhibitory and motor mechanisms, when 
they arise by sympathetic nerve channels. 

3. On the heart. — In the study of the action of epinephrine on 
the isolated heart, it is abundantly shown that it produces an increase 
in the rhythm and also in the amplitude of the contractions. This 
effect is true for both the frog heart and for the mammalian heart. 



<2r@Eye 

Submaxillar?/ 
Parotid 




Visceral blood vessels 

Stomach 

Liver 

Pancreas 

Intestine 

Kidney 



Colon-rectum 
Urinary bladder 
Genital organs 



Fig. 41. — Diagrammatic representation of the paths of the autonomic nervous dis- 
tribution. Modified from Meyer and Gottlieb. 

A perfusion through the frog heart isolated from the central nervous 
system shows this acceleration accompanied by an increase in ampli- 
tude. In the perfused isolated mammalian heart the amplitude x>f the 
contractions will often be doubled or even trebled. The rate may follow 
the increase in amplitude or may remain constant. There is great 
variation in individual experiments. 

If the heart is studied in the intact mammal, then the picture 
is somewhat different. At the stage of maximal blood-pressure, in- 
stead of an increase in heart rate there is a decrease, a fact attributed 
to the increase in tonic activity of the vagus center. The rise of 



158 EPINEPHRINE 

blood-pressure is itself sufficient to stimulate the vagus center — a fact 
that has long since been known. Hence many authors consider this 
vagus slowing under adrenaline as purely a secondary effect. The 
matter cannot be said to be fully settled, for it seems that there is a 
questionable factor of direct medullary stimulation involved. In any 
case, the stimulating effect on the accelerator mechanism is far more 
powerful and the quickest to take effect as shown by the accelerated 
heart rate during the rapid. rise of blood-pressure. It is the pre- 
dominant factor in determining the major change in heart function 
under adrenaline in the intact animal. 

Cardiac muscle is itself directly stimulated by adrenaline. This 
is proved by experiments on isolated heart muscle. Strips of the terra- 
pin 's ventricle increase in amplitude and also in rate, under the influ- 
ence of solutions of adrenaline. The accelerator cardiac mechanism is 
absent or at most poorly developed in this animal, hence the favorable 
muscular effects cannot be explained by assuming a stimulation of the 
accelerator endings. 

4. Salivary glands. — The injection of adrenaline in mammals 
leads to an increased secretion of the salivary glands and of the 
lachrymal glands. The glands of the respiratory tract, in general, 
show acceleration in function, though there is apparently no stimula- 
tion of the sweat glands. Adrenaline stimulates the sympathetic 
secretion. This action of the drug is relatively unimportant. 

5. On gastric and intestinal movements. — Brodie and Dixon 1 
present a table showing that adrenaline influences all those organs 
that respond to sympathetic stimulation. The important function 
in the sympathetic control of the gastric and intestinal movements is 
through inhibitory nerves. These are primarily stimulated by adrena- 
line. Dale, 2 in the comparative table presented below, finds that 
adrenaline produces the same inhibitive action on the alimentary 
tract after ergotoxine as before poisoning by the drug. 

The ileo-cecal sphincter (Elliott) is strongly contracted by adrena- 
line, though adjacent muscles on either side are inhibited by the 
drug, a result in complete accord with sympathetic stimulation. 

6. Adrenaline on the uro-genital apparatus. — Adrenaline pro- 
duces on the bladder and the uterus of the mammal the same general 
effects as are produced by stimulation of the sympathetic nerves. 
This Dale has shown to be both stimulative and inhibitive for the 
uterus, owing to the twofold sympathetic innervation. 

1 Brodie and Dixon: Journal of Physiology, Vol. XXX., p. 476, 1904. 

2 Dale, II. II.: Journal of Physiology, Vol. XXXIV., p. 163, 1906. 



ACTIOX OF EPINEPHRINE ON THE EYE 



159 



The Action of Adrenaline on Different Organs of the Mammalian Body in the Normal 
Animal, and after Ergot Poisoning. From Dale. 



Organ. 



Effects of stimulating the sympathetic 
nerve supply, or injecting adrenaline 
intravenously. 



Before ergot. 



After ergot. 



Arteries (cat, dog, ferret) 

(rabbit) 

Cardiac muscle 

Spleen (cat) 

Stomach (cat) • 

Small intestine (cat, dog, monkey). 

Large intestine (cat) 

Ileo-colic sphincter (cat) 

Internal anal sphincter (cat) 

Gall bladder 

Fundus of urinary bladder (cat). . . 
Fundus of urinary bladder (ferret) 
Base of bladder and urethra (cat). . 
Pilo-motor muscles 

Dilator iridis 

Uterus (cat, non-pregnant) 

Uterus (cat, pregnant) 

Uterus (rabbit), 

Uterus (monkey) 

Retractor penis (dog) 



M 
M 
31 
M 
I 
I 
I 

M 
M 
I 
I 

M 
M 
M 

M 

I or M and I 
M 
M 
M 
M 



I 
Nil or weak M 
Nil or weak M 
I 
I 
I 
I 
Nil 
I 
I 
I 
I 
Nil 
Nil 
Nil with adrenal- 
ine. Weak M with 
cervical sympa- 
thetic stimulation 
I 
I 
I (slight) 
I 
Nil 



M.— Motor effects. 



I.— Inhibitory effects. 



If the uterine motor nerves, which are dominant under certain 
conditions, are first paralyzed by ergotoxine, then injections of adren- 
aline stimulate the inhibitory nerves just as in the doubly innervated 
vascular regions. The uterus and vagina react together. 

7. On the eye. — The intravenous injection of adrenaline produces 
a marked dilation of the pupil of the eye together with the usual 
vascular constrictions. On the other hand, local instillation of 
adrenaline in the normal eye produces no pupillary effect (Radzwei- 
sky, 1898), a failure that has been difficult to explain. Meltzer and 
Auer, 1904, in studying rabbits found that if the cervical sympathetic 
nerves were cut then adrenaline produced vasoconstrictions in the 
ear, both when given intravenously and when introduced hypodermic- 
ally. The contractions of the vessels, under these conditions, came 
on later, were stronger, and lasted very much longer. The eye still 
responded as in the normal animal. After excision of the superior 
cervical ganglion the pupil of the eye was markedly dilated, not only 
by intravenous, but also by hypodermic and by local injections of 



160 



EPINEPHRINE 



adrenaline. This dilation did not occur immediately after excision 
of the ganglion, but only after an interval of 24 hours or more, and it 
occurred as late as three and one-half months. 

Undoubtedly the cervical sympathetic exerts a tonic mydriatic 
effect on the iris. Section of the nerve in the neck leads to a loss of 







Fig. 42. — The action of 0.1 mgr. adrenaline injected into the circulation of the cat. 
B. P. arterial hlood-pressure, lower tracing. The upper tracing represents the contrac- 
tion of the pregnant uterus. Note from the tahle, page 159 that adrenaline causes 
relaxation of the non-pregnant uterus. Time in seconds. From Dale. 



tone, hence to slight constriction of the pupil. Following excision 
of the ganglion the peripheral nerves will in time degenerate. Hence 
the mydriasis produced by injections or instillations of adrenaline at 
long intervals after the ganglion has been removed would seem to be 
dependent upon the local stimulation of the radial muscles. In 
what way the presence of the ganglion prevents this " paradoxical " 
action in the normal animal is not clear. The oculo-motor nerve is 
not influenced by adrenaline. 



ACTION OF EPINEPHRINE 



161 



8. Glycosuria. — When adrenaline is administered to a mammal 
in stimulative quantity sugar appears in the urine. This is attributed 
to an increase in the glycogenolysis of the liver. The studies of Paton 
show that the glycosuria does not have its origin in the kidney. By 
operations on the rat which is a favorable animal for this purpose, 
it has been shown that extirpation of the suprarenal glands leads to 
the elimination of the stored glycogen from the liver. Schwarz 1 
found from 2.44 per cent, to 5.07 per cent, glycogen in the livers of 
normal rats. After complete epinephrectomy, the two adrenals being 
removed in successive operations, the liver was never found to con- 
tain more than a trace of glycogen — in seven epinephrectomized livers, 
two only showed traces of glycogen. 



IV. 

General Discussion of the Action of Epinephrine. 

Epinephrine, like the members of the pilocarpine group, produces 
its action chiefly at the terminal fibers of a special group of nerves, 
in this case the strictly sympathetic nerves, such as the accelerators 
of the heart, the inhibitory nerves of the stomach and intestine, etc. 




Fig. 43. — Intestinal strip beating in inactive blood which was removed at o. Blood 
from adrenal veins substituted at b, and removed at c. Contractions restored in inact- 
ive blood, blood removed at d; then blood from renal vein (same animal) added at e. 
Time in half minutes. From Cannon and de la Paz. 

But of all the reactions the most specific and characteristic is the 
profound general stimulation of the vasomotor nerves. Here again 
we have a marked specificity of action and one which has a profound 
influence on the normal function of the body. 



1 Schwarz, Oswald: Pfliiger's Archiv, Vol. CXXXIV., p. 259, 1910. 



162 EPINEPHRINE 

Cannon and de la Paz, 1 1911. advanced the interesting view that 
the suprarenal gland is of specific physiological importance in connec- 
tion with the function of the sympathetic system, particularly in times 
of stress. They observed that cats, dogs, and other animals when in 
fright show dilation of the pupils, erection of the hairs, inhibition of 
alimentary movements, etc. — typical sympathetic reactions. Under 
these conditions they say there is a strong stimulation of the supra- 
renal glands, whereby the secretion of epinephrine into the blood- 
stream is increased. This increase in turn reacts on the terminal 
structures of the sympathetic system in general to render physio- 
logical responses of the organs more effective. 

That the suprarenals markedly influence metabolism is indicated 
by the disturbances of the glycogenic function upon their removal, 
or upon the injection of epinephrine. The same significance at- 
taches to the disturbances of function that occur in disease of the 
glands, as, for example, in Addison's disease. Normal suprarenal 
glands contain from 2.5 to 3 per cent, adrenaline, whereas diseased 
glands may have little or none of this active principle. 

The transient effect of epinephrine has been difficult to explain. 
As a matter of fact, the direct effect of epinephrine on cardiac mus- 
cular tissue is more persistent. The observations of Meltzer and 
Auer, already referred to, on the blood vascular constrictions and 
the mydriasis after excision of the superior cervical ganglion show 
that after this operation the action of adrenaline is very persistent, 
lasting one hour and often more. It would seem, therefore, that the 
transient effect is dependent in some way not fully explained upon 
the reactions through the sympathetic system. Of course, in paralysis 
or other loss of function of the nervous system the more enduring 
effect may be expected, and is to be kept sharply in mind by the 
clinician. 

The disappearance of the vasoconstriction was at first thought to 
be due to oxidation of the adrenaline, either directly by the tissues 
or through the influence of the alkalinity of the blood and tissues. 
But it has been shown that the blood of an animal that has received 
a large dose of epinephrine and has apparently recovered from the 
effects still is capable of producing the adrenaline reaction in a 
second animal. Adrenaline injected into the leg of a rabbit, in which 
the circulation is obstructed by a ligature, will produce the typical 
reactions in the body when the ligature is removed. Contact with 

1 Cannon, W. B., and do la Paz: American Journal of Physiology, Vol. 
XXVIII, p. 64, 1911. 



SUMMARY OF ACTION 163 

the tissues for one hour or more ought to suffice to oxidize the 
epinephrine if that accounted for its short reaction in the body. 

The evanescent effect of epinephrine has been against its use as 
an ideal blood vascular stimulating agent for therapeutic purposes. 
But many conditions arise, disturbing the efficiency of the sympathetic 
nervous mechanism, such as a general vasomotor depression with atony 
of the blood-vessels. Here intravenous perfusions of warm saline 
containing not more than one drop of standard solution of adrenaline 
hydrochloride per 100 cubic centimeters, has proven extremely bene- 
ficial in overcoming the splanchnic vascular dilation in vasomotor 
shock. The peripheral action of epinephrine is beneficial even when 
the splanchnic dilation takes place from central shock. This would 
seem to indicate that epinephrine is a valuable agent in the trans- 
fusion of saline in this type of depressed sympathetic nerve function. 



Summary of Action. 

Epinephrine intravenously injected produces a tremendous rise 
of blood-pressure. When given hypodermically the effect is slight 
unless the dose be very large — one hundred times as great as the 
intravenous dose. But it is effective and prolonged, especially in 
operative or degenerative removal of the peripheral sympathetic 
ganglia. The rise of blood-pressure is produced by strong stimula- 
tion of the arterioles primarily through the endings of the vasomotor 
nerves, or in cases of paralysis of the post-ganglionic nervous mechan- 
ism through direct stimulation of the muscular tissue. 

Arterial constriction occurs through the body, but is greatest in 
the splanchnic area. The heart itself is stimulated through the ac- 
celerator nerves and by an increase in contractile power of the heart 
muscle. This effect is somewhat counteracted by the increase in 
tone of the cardiac inhibitory center, which effect is at its maximum 
at the time of maximal blood-pressure. Other organs respond to 
epinephrine by an increase of function of the type produced by the 
stimulation of the sympathetic nervous mechanism. The organs of 
chief importance are the eye, in which dilation of the pupil occurs on 
intravenous injection of epinephrine, or in local application or sub- 
cutaneous injection after removal of the superior cervical ganglion; 
the stomach and intestine, in which there is an inhibition of peristalsis 
accomplished through stimulation of the sympathetic inhibitory 
nerves; and on the bladder, uterus, and spleen, where similar effects 



164 EPINEPHRINE 

are produced. Metabolism is sharply influenced by adrenaline, shown 
primarily by the increase in the glycogenolysis of the liver. 

This active principle is produced by the suprarenal gland under 
the nervous control of the sympathetic nervous system. The alkaloid 
is discharged into the blood-stream and distributed especially to the 
nerve endings of the sympathetic fibers throughout the body which 
it specifically stimulates, and to the muscular and glandular tissues 
controlled by these fibers. Epinephrine is largely consumed in the 
body, though when excessive quantities are present, small amounts 
are excreted through the urine. 



CHAPTER XVII. 

THE ERGOT SERIES. 
I. 

Historical and Chemical. 

The fungus, Claviceps purpurea, which grows chiefly on rye, con- 
tains a series of pharmacologically active principles more or less 
toxic. Preparations of ergot have been used in medicine since the 
sixteenth century. The active principles have been difficult to isolate 
but have been the subject of numerous careful studies. The first 
important investigation which should be mentioned is that of Kobert * 
in 1884. Kobert isolated three substances, to which he gave the 
names ergotinic acid, sphacelinic acid, and cornutine. Kobert 's ac- 
tive principles have been proven to be in all probability impurities. 
However, he showed that ergot contained two types of toxic sub- 
stances, one of which leads to chronic disintegration and sloughing 
of the tissues, the other to more acute conditions associated with 
high blood-pressure and accompanying nerve symptoms. 

In chronic ergotism, resulting during severe epidemics which have 
occurred in certain parts of Europe following the use of infected 
rye bread, these two types of intoxication have occurred. 

Through the mutually supporting chemical and pharmacological 
work of Barger and Dale, 2 in combination with various associates, 
we now know that the activity of ergot is due primarily to three 
chemical substances. These chemicals are ergotoxine, isoamylamine, 
and the more strongly toxic parahydroxyphenylethylamine. The 
latter approaches adrenaline in the character of its action. 

Ergotoxine, CsbH^ObNb 
Isoamylamine, £^f)CH.CH a .CH,.NH 9 

1 Kobert, R.: Arch. f. Path. u. Pharm., Vol. XVIII., pp. 316-380, 1884. 
"Barger, G v and Dale, H. H.: Bio-chemical Journal, Vol. II., pp. 240-299, 
1907; Journal of Physiology, Vol. XLL, p. 19, 1910. 

165 



166 THE ERGOT SERIES 



Parahydroxyphenylethylamine, HO^ \CH 2 .CH,.NH 2 

HO 
Adrenaline, Ho/ \cH(OH).CH 3 .NH.CH 3 . 



Isoamylamine and parahydroxyphenylethylamine, the latter known 
under the trade name of tyramine, were isolated from ergot by the 
methods used in isolating the same substances from putrid meats, 1 
and it is interesting to note that the probable origin is similar in 
the two cases, namely, from leucine in the first instance and from 
tyrosine in the second. The pharmacological reactions are identical 
in kind. 

The complex content of ergot preparations readily decomposes, 
hence such preparations rapidly change in the intensity of their 
physiological actions, a factor that should be taken into account in 
the therapeutic application of the drug. 

II. 

Outline of Pharmacological Action. 

The pharmacological action of individual ergot preparations varies, 
but when preparations of the crude drug are used the following 
primary effects occur: 

1. Stimulant effects on plain muscle organs, prominent among 
which are the circulatory system, the alimentary canal, and the uro- 
genital system. 

2. Specific toxicity to the motor types of myo-neural junction 
(ergot oxine) . 

3. Toxicity to protoplasmic structures in general. 

4. Parahydroxyphenylethylamine produces a sympathomimetic 
activity comparable to epinephrine. 

5. Ergotine produces primary stimulation followed by paralysis 
of the myo-neural junction. 

III. 

Details of Pharmacological Action. 

i. The action of chemically pure principles. — The exact action 
of the ultimate principles in ergot is still under some discussion in the 

1 Barger, G., and Walpole, G. S.: Journal of Physiology, Vol. XXXIX., p. 343, 
1909. 



ERGOTOXINE 



167 



literature, but accepting the work of Barger and Dale, as indicated 
above, we may attribute the characteristic ergot symptoms, first, to 
ergotoxine, which is responsible for the gangrenous degenerations at- 
tributed to ergot, and second, to the parahydroxyplienifletJiylamine, 
the blood-pressor and other involuntary motor effects. 

2. Ergotoxine. — Ergotine produces " ataxia, dyspnea, saliva- 
tion, gastro-intestinal irritation, and gangrene." It also produces 
stimulation of those organs containing smooth muscle, especially the 




Fig. 44. — The action of ergotoxine perfused through the frog's heart. The rate la 
little changed though the amplitude is slightly increased and remains high after the 
normal Ringer's solution is returned. New tracing by Summers. 



uterus and the arteries. In these latter paralysis follows at a later 
stage of its action. It is an interesting fact that the extreme toxicity 
of ergotoxine is lost by its dehydration, in the crystalline ergotinine 
C 85 H 89 O s N 5 . It is the ready transformation between these two sub- 
stances to which is ascribed much of the variability in current prepara- 
tions of ergot. Barger and Dale believe that the active ergotoxine 
has been present as an impurity and accounts for the action ascribed 
to many of the specific substances that were prepared earlier in the 
history of the study of ergot. 

3. Isoamylamine. — This active principle has been tested out by 
Dale and Dixon, who found that it was a positive blood-pressure 
producing substance. Its reaction is not so vigorous as the other 
active ergot principles, and its quantity is relatively small in ergot, 
hence it may be passed without special emphasis. 

4. Parahydroxyphenylethylamine. — This substance was isolated 
from ergot by Barger and Dale in 1909, and was carefully studied 



168 



THE ERGOT SERIES 



pharmacologically by Dale and Dixon. They found it to be a very 
strong pressor principle. It caused a vigorous rise of blood-pressure 
when injected intravenously in as low as two-milligram doses. It also 
sharply stimulated the amplitude and rhythm of the heart, the con- 
tractions of the spleen, the uterus, and of muscular portions of the 
urinary apparatus. The action is indeed very similar to that of 




Fig. 45. — The influence of isoamylamine on strips of muscle from the terrapin heart. 
The upper tracing is a ventricular, the lower a sinus-auricular strip. The strength of 
solution 15 per cent, in physiological saline. The most striking change is the marked 
increase in tone and suppression of the rhythm in the ventricle. Both strips exhibit a 
strong rhythm in the late after-period. New tracing by Stone. 



adrenaline, producing both the motor and inhibitory effects charac- 
teristic of nerves of the sympathetic system. The motor effects are 
more powerful than the inhibitory. However, the stimulating action 
of the drug is many times less intense than that of adrenaline. 

5. The action of extracts of ergot. — The pure principles of ergot 
have not yet been fully accepted for general use. Therapeutists still 
find the principal available preparations to be the older Galenic ex- 
tracts, or the more or less purified extracts. The extracts of ergot 
contain beside the pure principles mentioned above traces of a num- 



ACTION OF ERGOT ON THE UTERUS 169 

ber of more or less toxic substances, some of which have deleterious 
effects, particularly on the heart. As these principles vary in quantity 
in different preparations the extracts should, like digitalis, always be 
physiologically standardized and should be used within a reasonable 
time after this standardization. 




Fig. 46. — The effect of 2 mgrs. p-hydroxyphenylethylamine given intravenously. 
Spleen volume upper, and blood-pressure lower curve. Time in 10 seconds. Pithed cat. 
From Dale and Dixon. 

The most typical and characteristic influence of ergot is the pro- 
duction of an increased action of smooth muscle tissue. The thera- 
peutic value of the drug depends especially on this reaction as regards, 
first, the function of the uterus, and second, the reactions of the 
blood vascular system. 

6. The action of ergot on the uterus. — For many years ergot 
has been used for its beneficial effect upon the contractions of the 
uterus during parturition. When given in therapeutic quantity it 
leads to an increase in the expulsive uterine contractions during child- 
birth, especially when the uterine wall is reacting weakly. In ex- 
cessive or toxic doses the normal peristaltic contractions may become 



170 



THE ERGOT SERIES 



tetanic in character, which, of course, is detrimental to the normal 
function at this time. Over-violent contractions against the volume 
of the fetus may in fact lead to laceration and rupture of the uterus, 
as well as asphyxiation of the fetus itself. 

A second obstetric use of ergot is to aid in the post-partum con- 
tractions of the uterine wall in order that the open and bleeding 




Fig. 47. — The effect of 2 mgrs. of parahydroxyphenylethylamine on the isolated apex 
of the pregnant uterus of the cat. The drug was added at the ! and changed to pure 
Ringer's solution at the J . Contractions, down strokes. Time in 10 seconds. From 
Dale and Dixon. 



uterine sinuses may be somewhat closed during the critical time that 
these lacerated surfaces are being occluded through blood coagula- 
tion, etc. There is no doubt that a favorable exhibition of the drug 
is of value in this connection, though its excessive use may lead 
to an after-paralysis and relaxation with post-partum bleeding. 

In following the reactions of the uterus to ergot it must be kept 
in mind that the organ has a double innervation, stimulative motor 
nerves, chiefly through the hypogastric and the inhibitive nerves, in 
part from the sacral region. The relative physiological control of 
these nerves over the organ varies according to the state of the uterus. 
Numerous experiments have shown that the pregnant uterus is much 



ACTION OF ERGOT ON THE CIRCULATORY SYSTEM 171 

more amenable to the motor nervous control than the non-pregnant. 
Ergot, for example, often causes relaxation of the virgin uterus, 
whereas it produces strong contraction of the pregnant uterus. The 
ergotoxine first stimulates, then paralyzes the utero-motor apparatus, 
apparently paralyzing at the myo-neural junction. After this paral- 
ysis epinephrine, which stimulates both motor and inhibitory uterine 
nerves, now produces only inhibition. 1 The ergotoxine constituent of 
extracts of ergot may through this latter effect modify the pressor in- 
fluence of the parahydroxyphenylethylamine. 

7. The action of ergot on the circulatory system. — Sollmann and 
Brown 2 have exhaustively studied the influence of ergot on the 
circulatory system, showing the remarkable variation in the intra- 
venous effects of these preparations. They more often found a fall 
of blood-pressure on intravenous injection of ergot than the contrary. 
This, in view of the well-established blood pressor action of both 
ergotoxine and of parahydroxyphenylethylamine, shows the inherent 
danger of reliance on extracts of ergot. The logic of the case would 
indicate the greater reliability of the chemically pure preparations. 
The therapeutically valuable principles of ergot produce a tremendous 
rise of blood-pressure by a stimulation of the vasoconstrictor nerve 
endings. The vascular contraction is similar in character, but smaller 
in amount and more prolonged than that produced by epinephrine. 

The gangrene that follows the use of certain ergot preparations 
has been explained on the ground that the vascular spasm of such 
vascular peripheral organs as the ear and the cockscomb is due to the 
fact that the prolonged contraction shuts off the blood-supply to 
such an extent as to cause asphyxiation and degeneration of the 
tissues. Histological studies have shown obliteration of the cavity 
of the blood-vessels accompanied by hyaline degeneration. However, 
this explanation may account only in part for the gangrene effects, 
since many preparations of ergot contain considerable quantities 
of saponine-like bodies. 

8. On the heart. — The cardiac action is decidedly strengthened 
by ergot, especially is the amplitude of the contraction of the ventricles 
increased. This is shown not only on the heart in place, but on the 
isolated heart (Sollmann and Brown), and is therefore to be ascribed 
to peripheral action, and is due to stimulating effects on the accelerator 
nerve endings. In contrast with the cardiac stimulation of alkaloids 

1 Dale, H. H.: Journal of Physiology, Vol. XXXIV., p. 163, 1906. 

2 Sollmann, Torald, and Brown, E. D. : Journal of the American Medical As- 
sociation, Vol. XLV., p. 229, 1905. 



172 



THE ERGOT SERIES 



such as epinephrine, it is noted that the ergot stimulation is much 
more persistent and prolonged. Epinephrine stimulates the accelerator 
nerve endings in cardiac muscle, and the resulting physiological 
changes are quickly developed and profound in volume though rel- 




Fig. 48. — The effect of 0.2 mgr. of parahydroxyphenylethylamine on the isolated 
heart of the rabbit. Time in 1-4 seconds. From Dale and Dixon. 

atively short in duration. The cardiac action of the active prin- 
ciples of ergot is somewhat more prolonged, though otherwise similar 
to epinephrine, a fact which undoubtedly is to be ascribed as chiefly 
due to the parahydroxyphenylethylamine constituent. However, the 




Fig. 49. — The effect of 0.2 cc. — solution of isoamylamine hydrochloride on the 
isolated heart of the rabbit. Time in 2 seconds. From Dale and Dixon. 



isoamylamine constituent also stimulates after a very brief muscular 
depression, as shown in the figure. Augmentative influence on the 
heart produces a strong percentage of the rise in blood-pressure. It 
is the combination of the two factors, increase in peripheral resist- 
ance and cardiac augmentation, that accounts for the firm, hard 
pulse in ergot poisoning. In those preparations of ergot which have 
cardiac depressing principles the stimulating effect may be counter- 
acted by the direct cardiac muscular depression. 

9. Action on the alimentary canal. — Ergot leads to a marked 
increase of the peristalsis of the alimentary tract. Not only does 
this systemic effect result, but local irritations may lead to pro- 



ACTION ON OTHER PHYSIOLOGICAL MECHANISMS 173 

nounced insalivation, vomiting, and purging. The peristaltic action 
is ascribed largely to the effect of ergot on the nervous mechanism 
controlling alimentary peristalsis, though a direct stimulation of the 
smooth muscle has been described. Gangrenous foci are also found 
in the mucous membrane and walls of the alimentary canal. These 
are due to the vascular stagnation and resulting local degenerations 
from the action of ergotoxine. 

10. Effect of ergot on other physiological mechanisms. — The 
nerve centers in the medulla are stimulated to some slight extent by 
ergot, though it has not always been clear whether or not these 
stimulations are the indirect effects of the change in vascular supply. 

The secreting glands are influenced to a greater output, the eye 
exhibits a marked contraction of the pupil, and the urinary bladder 
is thrown into motor activity, all by intravenous injections of ergot. 
These effects are doubtless due primarily to the two most active con- 
stituents, ergotoxine and hydroxyphenylethylamine. 



D. Drugs With Primary Activity On Smooth Muscle. 

CHAPTER XVIII. 

BARIUM CHLORIDE. 



Barium chloride, one of the inorganic salts, has a very pro- 
nounced influence on the circulatory system, an action in a way inter- 
mediate between that of digitalis and ergot. 

II. 

Outline of Pharmacological Action. 

Barium chloride is a very toxic substance and produces toxic 
change in the physiological reactions in most parts of the body, sum- 
marized as follows : 

1. A pronounced stimulation, followed by a toxic paralysis of the 
central nervous axis, especially of the medulla and cord. 

2. Vascular constriction by direct stimulation of the muscles of 
the arterioles. 

3. Increase in the heart rate, with fibrillation in the toxic stage. 

4. Respiratory acceleration from medullary stimulation. 

5. A toxic contraction of skeletal muscles, with delay in the re- 
laxation phase. 

6. Cathartic and diuretic action. 

7. Local irritation and toxic necrosis of tissue. 

III. 

Details of Pharmacological Action. 

i. Barium chloride on the circulatory system. — On the heart: 
The most striking influence of barium chloride is that on the circula- 
tory system. The function of the heart is decidedly influenced. In 
therapeutic quantity introduced into the general circulation, the 
heart beats stronger but slower, but a greater quantity (30 mgr. 

174 



ACTION ON THE HEART 175 

intravenous in a dog) leads to a tremendous increase in the heart 
rate. 

On the isolated perfused heart the contractions are more 
vigorous and far more rapid than under normal conditions. The 
peripheral action of barium chloride is directly on cardiac muscle. 
Isolated strips of ventricle contract with greater amplitude and 
with increased rhythm. There is a tendency to great increase in 
tone, so that the muscle enters a strong systolic contracture. If the 
concentration of the salt be too great or it act too long, the contrac- 



d'»ltliimil> %m 



WMWw 



Fig. 50. — The effect of 5 mgrs. of barium chloride on the blood-pressure after paral- 
ysis of the vasomotor nerve endings by 150 mgrs. of chrysotoxin. This demonstrates 
that the barium chloride acts directly on the smooth muscular tissues of the arterioles. 
From Dale. 

tions cease to be coordinated. Independent rhythmic centers are 
set up over the heart, leading to fibrillation. This effect of barium 
chloride is produced by 0.01 per cent. (1 in 10,000) in physiological 
saline. Perfusions of barium chloride solutions through the isolated 
mammalian heart produce changes that are quite comparable to the 
muscular actions just described. The rhythm is increased, the volume 
of the contractions is greater, and there is a marked tendency toward 
fibrillation. 

When the heart is studied in its normal relations it shows a de- 
cided slowing, due to the preponderant influence of barium chloride 
on the cardiac inhibitory center. But if the vagus nerves are first 
cut, then there is a primary acceleration of rhythm. 

2. On the peripheral arterioles. — Barium chloride solutions in- 
crease the peripheral resistance of the circulatory bed by contractions 
of the arterioles. The reaction is due in part to stimulation of the 
vasomoter center, but in larger part to peripheral muscular action, 
as shown by the great decrease in volume observed in the plethysmo- 



176 BARIUM CHLORIDE 

graphic measurements of isolated organs. The contractions occur 
also after drugs which poison the nerve endings and are therefore 
to be ascribed to a direct stimulation of the smooth muscle in the 
walls of the arterioles. 

3. Barium chloride on the alimentary and uro-genital muscle. — 
The alimentary canal is actively stimulated to increased peristalsis. In 
both the gastric and the intestinal regions the changes are very pro- 
nounced. This influence is in large measure a direct action of the 
barium chloride on the smooth muscle walls. For the same reason 
the walls of the uterus and urinary bladder have their typical mus- 
cular movements decidedly increased. 

4. On skeletal muscle.- — Skeletal muscle is rendered more un- 
stable and irritable by barium chloride. "When a test is made by a 
series of contractions of an isolated muscle it is found that the 
amplitude of the contractions is sharply increased in the earlier 
numbers of the series, while contracture from delayed relaxation 
makes its appearance later in the series, but long before the muscle 
is exhausted. 

5. On the central nervous system. — Barium chloride is a toxic 
substance for the nervous tissue. Its influence is characterized by 
prolonged and violent stimulation with paralysis in the later stages. 
Practically all the basic nerve centers have their irritability sharply 
increased. The spinal cord, for example, is far more sensitive to 
reflex stimulation and shows a tendency to the discharge of reflex 
spasms that approach the character of tetani. 

Most typical nerve changes are shown by the disturbance of func- 
tion of the reflex centers of the medulla. The vasomotor center is 
increased in tone and stimulated, the cardiac inhibitory center stimu- 
lated, and the influence on the respiratory center leads to a great 
acceleration of respiratory rhythm and amplitude. Intravenous in- 
jections of non-toxic quantities of barium chloride produce on the 
respiratory center at first a great acceleration in rhythm, which may 
amount to as much as 100 to 150 per cent, of the preceding normal. 
This enormous increase of rhythm is associated with a great increase 
in respiratory amplitude. This stage is followed by a marked diminu- 
tion in amplitude, usually with the prolonged maintenance of the 
supra-normal rate. Recovery is slow and characterized by irregularity 
of respiratory rhythm. 

6. The local action of barium salts. — Barium salts are extremely 
toxic. "When brought into contact with mucous membranes or in- 
jected hypodermically they tend to produce disintegration and necrosis 



THERAPEUTIC INDICATIONS 177 

of the local area. This is due to a toxic action on protoplasm in 
general. 

7. Therapeutic indications. — Pharmacologically the reactions of 
barium in the body strongly suggest a comparison with the digitalis 
series. Various attempts have been made to introduce it into thera- 
peutics with indifferent success, chiefly from its dangerous toxic after- 
effects. It has been cautiously exhibited in conditions of extreme 
atony, especially of the circulatory system. Barium chloride was 
recognized in 1910 and 1911 only by insertion into New and Non- 
official Remedies, with the following description under the caption, 
* l Actions and uses ' ' : ' ' Barium chloride is a toxic substance, its most 
striking effects being exerted upon muscle tissue, especially unstriped 
and heart muscle. In large doses it affects the spinal cord and me- 
dulla. By actively stimulating peristalsis, through action on the mus- 
cle wall, and by its direct irritant action, it readily produces vomiting 
and purging. It strengthens the cardiac contraction by direct action 
of the heart muscle, and by this means and still more by direct action 
on the vessel walls it greatly increases blood-pressure, acting like 
digitalis. It acts on the muscles like veratrine. It first greatly excites 
and then paralyzes the spinal cord and medulla. Given in very 
dilute solution, absorption is small and the barium is deposited in 
the bones. Injected intravenously it causes tonic and clonic spasms, 
because of stimulation of the spinal cord and medulla. 

" In fatal doses it causes hemorrhages into the stomach, intes- 
tines, and kidneys. 

" Its clinical use has been attended with little success, chiefly 
because of the gastro-intestinal irritation and high toxicity. It has, 
however, been used in cardiac disease with insufficient blood-pres- 
sure, as a general tonic, and with less reason in tremors, in scleroses 
of the central nervous system, internally and locally in varicose 
veins, etc. Its use is attended with considerable danger." 



CHAPTER XIX. 
• THE NITEITES AND THE NITROGLYCERINES. 

I. 

Chemical. 

As illustrations of a group of drugs acting particularly on the 
circulatory system, but to produce effects of depression of function 
just the opposite of ergot, barium chloride, etc., the nitrites form 
the most important example. 

Sodium nitrite, NaN0 2 , is a soluble salt. Amyl nitrite is a highly 
volatile, amber-colored liquid, which can be taken as a representative 
of the derivatives of the methane series, in which the alkyl is attached 
by an atom of oxygen, as shown in the formula, CH 3 O.NO, etc. The 
tri-nitrate of glycerine, or nitro-glycerine, C 3 H 5 (N0 3 ) s . This sub- 
stance is readily decomposed in the alkaline fluids of the body, giv- 
ing off nitrites and nitrates, the latter being inactive in small 
quantities, while the former give rise to the usual nitrite functional 
reactions. 

II. 

Outline of Pharmacological Action. 

1. Marked depression of blood-pressure produced through (a) 
a decrease in the functional activity of the smooth muscle, and (b) 
depression of the cardiac nervous mechanism. 

2. The formation of methemoglobin. 



III. 

Details of Pharmacological Action. 

i. On the circulatory system. — The most characteristic physio- 
logical change produced by the nitrites is that of relaxation of mus 
cular tissue, and particularly in the circulatory and respiratory 
mechanisms. When sodium nitrite is given intravenously, or amyl 
nitrite given either intravenously or by inhalation, there is a marked 
and prolonged fall of blood-pressure. This circulatory effect is pri- 

178 






DETAILS OF PHARMACOLOGICAL ACTION 179 

marily due to dilation of the arterioles. The skin is flushed and the 
great vascular beds in the abdominal viscera are congested. 

The perfusion of isolated organs is accompanied by a similar 
evidence of peripheral dilation. There is a more rapid outflow of 
the perfusion fluid, and if the organ be inclosed in a plethysmo- 




Fig. 51. — Showing tho action of nitrites on the form of the human pulse. A, 
normal pulse ; B, immediately after amyl nitrite vapor ; C and D, successive later stages 
in the return to the normal. 

graph, increase in volume occurs. If the organs be studied in their 
normal relations, as, for example, portions of the abdominal viscera, it 
can be shown that the nervous mechanisms are still functional, though 
less actively so. Stimulation of the splanchnic nerve produces a 
slight constriction of its terminal visceral bed. This contriction is 
less pronounced than in the normal, a fact, which, together with those 
related above, leads to the conclusion that the action of the nitrites 
is on the smooth muscle itself. 

2. On the heart. — Dilation of the blood-vessels, associated with 
fall of blood-pressure produces a physiological condition, which acts 
as a stimulus to increase the heart rate. Increase of heart rate is 
also brought about by any condition which diminishes the tone of 



180 NITRITES AND NITRO-GLYCERINES 

the vagus center, or, on the other hand, increases the contractile 
power of the cardiac muscle, as by barium chloride. 

When the nitrites are given the heart rate is sharply increased, 
but the amplitude of the contractions is practically unchanged. In 
studies of the isolated hearts of both the frog and the mammal, the 
increase of rate is less marked, but enough to indicate that the 
nitrites do slightly add to the irritability of cardiac muscle, though 
this effect is accomplished only by very minute doses. The stronger 
action of the nitrites is to depress cardiac muscle, much in the same 
way as it depresses smooth muscle. 

3. On the respiratory apparatus. — Nitrites have proven to be 
active depressants of muscular contractions in the respiratory ap- 
paratus. The drug acts directly on the smooth muscle of the bron- 
chioles, producing a relaxation of these muscles and dilation of the 
bronchioles. This effect is of value in clinical conditions, such as in 
asthma. Respiratory acceleration is generally noted, an effect which 
is due in mild extent to stimulation of the respiratory center. The 
depressed circulation through the respiratory center has a secondary 
effect, which must not be forgotten in this relation, an effect which 
is thought by some to be adequate to explain the acceleration noted. 

4. The formation of methemoglobin. — The nitrites are methe- 
moglobin formers. There is not the disintegration of the corpuscles 
to the extent noted in pyrogallol poisoning. 

IV. 
Condensed Summary of Action. 

The nitrites and the nitrite liberators are of peculiar value in 
that they produce relaxation of structures depending for their action 
upon smooth muscle. For example, the blood-pressure falls from 
arteriole dilation, and the effect is accompanied by a direct depres- 
sion of the function of the smooth muscles of the arteriole walls. 
The heart is accelerated, largely from depression of the inhibitory 
mechanism, but in part through an initial though slight increase of 
irritability of cardiac muscle. Respiratory spasms of the bronchioles 
are relieved by relaxation of their smooth muscle. There is some 
toxic formation of methemoglobin accompanied by the secondary 
symptoms, which result from a lack of sufficient oxygen carried by 
the blood. 

Nitrites in therapeutic quantity are peculiarly valuable to relieve 
smooth muscle spasms wherever they occur throughout the body, as, 
for example, in asthma, angina pectoris, lead poisoning, etc. 



E Glucosides of the Digitalis Series. 

CHAPTER XX. 

THE DIGITALIS GROUP. 



Historical and Chemical. 

Under the digitalis group one may classify a series of plant and 
animal substances, which have a rather extreme toxicity to animal 




Fig. 52. — Digitalis purpurea?, Foxglove, the plant in full bloom, a flower about two- 
thirds size, and a section natural size. Baillon. 

tissues in general, and are particularly stimulative and toxic to the 
heart and circulatory system. 

181 



182 THE DIGITALIS GROUP 

The substances of this series are derived from a rather wide range 
of plants, of which the most important are members of the genera 
Digitalis, Strophanthus, and Scilla. Of a long series of genera yield- 
ing active principles, but of more or less secondary importance, may 
be especially mentioned Apocynum, Helleborus, Convallaria, Antiaris, 
and Erythrophloeum. 

For the most part these plants yield non-nitrogenous glucosides 
and resinous principles. The active substances of the digitalis 
species were first separated by Schmiedeberg x and have later been 
studied by several authors. The active principle of Strophanthus, 
strophanthin, has also been separated, and has a therapeutic value 
similar to that of digitalis. Of these substances the most important 
are: 

Digitalin. 

Digitalein. 

Digitophylline. 

Digitoxin. 

Strophanthin. 

Preparations of the glucosides readily decompose, giving rise to 
toxiresins, in which their physiological reactions are markedly 
changed in the general direction of increased toxicity. 



II. 

Outline of Pharmacological Action. 

The different active principles have somewhat varying effects in 
the body, but in general they all produce : 

1. In therapeutic quantity an increase in the function, and in 
toxic quantity paralysis of practically all the tissues in the body. 

2. Specific stimidation of the heart muscle. 

3. Stimulation of the cardiac inhibitory nervous meclvanism. 

4. Specific stimidation of peripheral arterioles, particularly strong 
on the splanchnic region. 

5. Stimulation of the vasomotor center of the medulla. 

6. A marked diuretic action. 

7. A tonic action on the central nervous system, and on endothelial 
and lymphatic tissues. 

1 Schmiedeberg: Arch. f. Exp. Path. u. Pharm., Bd. 3, S. 16, 1875. 



DETAILS OF PHARMACOLOGICAL ACTION 183 

8. Local irritation and inflammation when applied hypodermically, 
or to mucous surfaces. 

III. 

Details of Pharmacological Action. 

In the study of the details of the change in physiological function 
induced by the different members of this series we will take as a 
standard for comparison the action of soluble digitalis and of stro- 
phanthin. 

i. Action on the circulatory system. — Digitalis produces its pri- 
mary, one might almost say specific, action on the circulatory system. 
The therapeutic effects are (1) stronger and slower heartbeat, (2) 
general vascular constriction, and (3) a pronounced increase in blood- 
pressure. The details of these changes must be given before general 
discussion of their inter-relations. 

2. The heart. — Digitalis given to a living mammal by the mouth 
usually produces a stronger, slower, and more efficient beat of the 
heart. Keeping in mind the complicated nervous and muscular 
arrangements of this organ, we may summarize by saying that the 
direct cardiac effects of the digitalis series are : 

1. Stimulation of the cardiac muscle, producing increased ampli- 
tude and usually an increase of the rhythm of contraction, and a 
greater irritability of the tissue. 

2. Stimulation of the cardiac inhibitory nervous mechanism by 
strong direct action on the vagus center, together with weaker local 
action in the heart ganglia. This produces slowing and greater re- 
laxation of the heart. 

These two factors, i.e., the direct muscular effects and the vagus 
nerve effects, are diametrically opposed to each other, hence many of 
the characteristics of the heartbeat under digitalis in the body are 
to be interpreted through their algebraic addition. 

Secondary effects on the heart are produced because of the tre- 
mendous rise 4 of blood-pressure following the peripheral vasoconstric- 
tion. This rise of pressure in itself increases the irritability of the 
medullary centers, therefore the vagus tone, and produces a mechanical 
stimulation of the sensory end organs of the depressor nervous 
meehanism, which Eyster and Hooker have shown to be located in the 
walls of the aorta. 

An experimental analysis of the heart effects of digitalis can be 
made by studying -. 



184 THE DIGITALIS GROUP 

1. Isolated heart muscle. 

2. The isolated heart. 

3. The heart in situ. 

Isolated pieces of cardiac muscle, of the terrapin or of the cat, 
have their irritability sharply increased by members of the digitalis 
series — digitalin, strophanthin, etc. True, it requires a rather 




Fig. 53. — Action of digitalis on the cardio-inhibitory center. During the time 
marked 0.01 per cent, digitalin was perfused through the isolated brain of the terrapin, 
vagus nerves intact, general circulation isolated from the brain. At the point marked 
the right vagus was cut, the heart immediately escaped. Cutting the left vagus dur- 
ing this experiment induces no change in rate. Time in 5 seconds. New tracing by 
Peeler. 



stronger dose, but both the amplitude and the rate of the heart muscle 
contractions are favorably influenced. With a relatively strong dose 
the terrapin ventricular muscle has its systolic phase increased and 
its relaxation hindered so that a state of tonic contracture super- 
venes. 

3. The isolated frog's heart. — Perfusions of the isolated frog's 
heart show phenomena similar to those obtained from the muscle 
alone. The rhythm is slightly accelerated, but the greatest change 
consists in the increase in the systolic and decrease in the diastolic 
phase of the contraction. The net result is a tendency of the heart 
to remain in systole. In the tonic stage this condition becomes 
dominant. 

The contractions of the auricles of the perfused frog's heart arq 
much more complete, and the relaxations relatively more incomplete 
than is the case with the ventricle. However, in experiments a slight 
excess of mechanical pressure may obliterate this effect and the auricles 
will remain dilated. 

4. On the isolated mammalian heart. — The isolated mammalian 
heart studied by the coronary perfusion method is most instructive. 
Here very dilute solutions of soluble digitalin, 11 parts to 1,000,000 of 



ACTION ON THE ISOLATED MAMMALIAN HEART 185 

perfusing solution, produce a sharp increase in the amplitude with 
only slight, if any, variation in the rate. If the dosage be increased, 
then both amplitude and rate are strongly increased. These effects 
are interpreted as primarily muscular. With perfusion of a toxic 
concentration the heart becomes irregular in its rhythm. Independent 
rhythmic centers are set up in the ventricular muscle, together with 
arrhythmia of the auricles and ventricles. This condition comes on 
rapidly and ends in fibrillation and death in the systolic stage. 




Fig. 54. — Digitalis on the isolated mammalian heart, dog. The heart was kept 
contracting rhythmically hy coronary perfusion with oxygenated Ringer-blood, 1 to 3. 
During the time indicated by the signal marker 0.0005 per cent, of digitalis in Ringer- 
blood solution was perfused. The rhythm of the heart remained absolutely constant 
during the experiment. The increase in amplitude amounted to 14 per cent, just before 
perfusion of digitalis was stopped, but increased to 19 per cent, in a few seconds after 
the normal was re-established. Time in five seconds. New tracing by Kruse, Heldt, 
and Stewart. 

Strophanthin perfused through the isolated heart by the method 
of Bock produces little or no change in rate, but the volume of the 
beat is increased sufficiently to slightly raise the pressure. The toxic 
margin is very slight in this case, and in the toxic stage the heart 
becomes arrhythmic, the muscles fibrillating, and death follows with 
the heart in the fibrillation stage. 

5. The mammalian heart in situ. — We owe largely to Cushny * 
the details of the influence of strophanthin on the mammalian heart- 
studied in its normal position. The therapeutic action of digitalin or 
of strophanthin produces in the mammalian heart an increase in 
the systolic phase of the contractions of both the auricles and the 
ventricles. 

As a rule, with the change in amplitude there is a slowing of the 
heart rate. The individual contractions are more complete, that is, 
have both a greater amplitude and a greater relaxation, hence the 
filling and emptying of the heart is more efficient. This efficiency 

1 Cushny, Arthur R.: Heart, Vol. IV., p. 33, 1912. 



186 



THE DIGITALIS GROUP 



is twofold, i.e., increased diastole, therefore greater filling, and in- 
creased systole, therefore more effective discharge. This effect is 
accomplished by the twofold action of digitalis. (1) The direct mus- 
cular action increases the muscular contractions when they occur, and 
(2) the action of the vagus center holds in check the muscular effects 
and in the face of the muscular stimulus produces a greater dilation 
and more efficient filling of the cavities of the heart. 



TABLE I 

Experiment 1 of Cashny on a dog narcotized by morphine and curare, Myocardiograph 
attached to the left ventricle. 



Time. 


Number of 

contractions in 

10 seconds. 


Height of 

syntole from 

base line. 


Height of 

diastole from 

base line. 


Length 

of excursion 

of lever. 


Normal 

After 20 seconds 


35 
1 mg. strop 
35 
33 

28 

244 

22 


26 mm. 
hanthin injec 

27 mm. 
264 '• 
25 •« 
23 " 
20 " 


384 mm. 

ted into the j 

39 mm. 

43 - 
45 " 

44 " 
43* " 


124 mm 

ugular vein. 

12 mm. 


" 50 " 


164 " 

20 " 


"70 


" 90 " 


21 " 


" 110 " 


234 " 



The experiment shows slowing of the heart rhythm, with a more 
complete systole. There is much greater diastolic relaxation, there- 
fore a corresponding increase in the total excursion of the ventricular 
contractions. 

TABLE II 

Experiment 9 of Cashny, cat narcotized with morphine and acetone chloroform, atropine 

to poison the vagus. 





Rate in 
10 seconds. 


Contraction 
volume. 


Percentage 

increase in 

contraction 

volume. 


Output in 
10 seconds. 


Percentage 
increase in 
output per 
10 seconds. 


Before strophanthin 

After strophanthin 

Later 

Still later 


18 
18 
18 
18 


23 

27 
29 
30| 


174 

26 

33 


414 
486 
522 
549 


m 

26" 
33 







This experiment shows no slowing of the heart; in fact, no 
change in heart rate, but an increase in the amplitude of the con- 
tractions. Therefore the efficiency of the heart is markedly increased 
by direct action of strophanthin on the muscle walls. 



DIGITALIS ON THE PERIPHERAL ARTERIOLES 187 

As the therapeutic stage passes toward the toxic stage an interest- 
ing intermediate condition supervenes in the heart. The increase in 
the irritability of the muscle tends to break down the sequence and 
the rhythm within the heart, while the hyperirritable condition of 
the vagus center tends to hold the heart in inhibition. There will 
come at this time periods of quite rapid contractions interspersed 
with periods of very slow beats or even complete inhibition. The 
medullary and local nervous centers pass into the paralytic stage 
somewhat earlier than does the muscle, hence the direct cardiac 
muscle stimulation presently becomes dominant. More frequent 
series of rapid beats now occur, with an increase in efficiency of the 
heart as a pump. However, this condition does not last long, since 
arrhythmia soon sets in because of the increasing hyperirritability of 
the muscle. The contractions of the auricle at this stage are not 
always followed by contractions of the ventricle, nor are these two 
events in proper sequence. 

In addition to the change in irritability of the muscle substance, 
there is an influence of digitalis on the conducting substances of the 
bundle of His. There is evidence, chiefly therapeutic, to indicate 
that digitalis diminishes the rate of conduction through this special 
mechanism of the mammalian heart. In other words, digitalis in its 
tendency to produce slowing of the auriculo-ventricular interval ac- 
complishes an effect of more or less complete heart block. The me- 
chanical effect of the combined change in the muscular irritability and 
the depression of conduction in the bundle of His is a great irregu- 
larity in the blood-pressure. When, during the arrhythmia, the au- 
ricular and ventricular contractions happen to fall in sequence, there 
is a sharp rise of blood-pressure; when they are in opposite phase, a 
similar fall. The ultimate toxic result is increasing arrhythmia, 
inefficient contractions, fall of blood-pressure, and final paralysis and 
cardiac death. 

6. Digitalis on the peripheral arterioles. — Members of the digi- 
talis series produce a marked contraction of the arterioles throughout 
the body. This peripheral vascular contraction produces a tremendous 
increase in the peripheral resistance to the blood flow and a resulting 
great rise in blood-pressure, which may amount to from 50 to 100 per 
cent. 

The vascular constriction is most pronounced in the visceral organs 

of the abdominal region. This was especially investigated by Gottlieb 

ami Magnus x in 1902. These authors compared the action of the 

1 Gottlieb and Magnus: Arch. f. Exper. Path. u. Pharm., Vol. XLVIL, p. 135, 
1902. 



188 



THE DIGITALIS GROUP 




P^B 



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°fl„, ^a-S^St* 
be" gg gt^-fl a 

* eh.2 S S ° 

"t; a> Si a> fl »c— « 

S-SSa-asssH 

. a > as . o i2 w C 

S 5 o«*°Stl5 

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CO 



DIGITALIS ON THE PERIPHERAL ARTERIOLES 189 

different members of the digitalis series on the visceral organs — the 
spleen, the intestine, and the kidney, and on the peripheral regions, 
using the volume of the leg as an index. It was shown that the con- 
striction in the volume of the extremities produced by digitalin, 
strophanthin, convallaria, etc., produced a tremendous rise of blood- 
pressure, with vascular spasm of the spleen, kidney, and intestine. 
With the weaker members of the digitalis series the influence on the 




Fig. 56. — The effect of 12 mgr. strophanthin, intravenous, dog. From Gottlieb 
and Magnus. 

blood-vessels of the limbs is very much less than on the visceral organs. 
A quantity of strophanthin, therapeutically active for the viscera, has 
practically no direct influence on the blood-vessels of the leg. Gott- 
lieb and Magnus found that the volume of the limb even followed 
the rise of blood-pressure very closely, a result which they explained 
as the physiological reflex associated with a condition of increased 
pressure in the viscera. With digitoxin, on the other hand, the 
vascular spasm was marked in the vessels of the limb as well as in the 
visceral organs. When they excluded the abdominal circulation the 
peripheral arterioles contracted in the face of a rise of blood-pressure. 
It may be reiterated, therefore, that the digitalis substances pro- 
duce marked general arterial constriction, though this effect is less 
strong in the periphery than it is in the viscera. It is less vigorous 
with certain members, strophanthin, than with others, for example, 



190 THE DIGITALIS GROUP 

digitoxin. In this connection it must be recalled that these two great 
vascular regions normally act in physiological opposition under many 
physiological conditions. Therapeutic quantities of digitalin, stro- 
phanthine etc., which just call forth visceral constriction are apt to 
be associated with dilation of the blood-vessels of the periphery, a 
secondary effect called forth through the interactions of the ordinary 
physiological mechanisms. 

The analysis of the vasoconstrictor effects of digitalis was made 
in part by Gottlieb and Magnus. They isolated the organs studied by 
them from the central nervous system, and found that the vasocon- 
striction occurred in practically the same degree as before. Others 
have shown that after sectioning of the splanchnic nerves a marked 
diminution in the rise of blood-pressure results. It would seem, 
therefore, that there is some stimulation of the medullary vasomotor 
centers, though it may be relatively slight and at times insignificant. 

Gottlieb and Magnus did not determine on what part of the periph- 
eral mechanism the digitalis acted. Cushny x stated in 1897 : " I 
think the evidence is overwhelming that the rise in pressure in the 
arteries is to a considerable extent due to action on the muscular 
walls of the arterioles." This point was finally cleared by Dixon, 2 
who poisoned the terminal vasoconstrictor fibers with apocodeine. 
Digitalis following this drug still produced vasoconstriction, proving 
that there was a stimulating action on the smooth muscle in the walls 
of the blood-vessels. 

Very slight, if any, change in the resistance of the pulmonary cir- 
culation has been noted with digitalis. There is always a marked 
diminution in the output of blood flowing from the isolated heart, fed 
by coronary perfusion. This decrease is attributable to coronary con- 
striction. 

7. The action of digitalis on the central nervous axis. — It has 
already been stated that digitalis produces a sharp rise in the tonic 
action of the cardiac inhibitory center, the details of which have been 
presented. The vasomotor center also is stimulated, though apparently 
in less degree. Other medullary centers show some slight increase in 
tonic activity, especially the respiratory, as indicated by the change 
in respiratory rate and depth. Mackenzie states that in clinical treat- 
ment " the most frequent nervous symptom was headache," some- 
times so severe as to stop the use of the drug. Perfusions of digitalis 
in experiments on the circulatory system of lower animals with intact 

1 Cushny, A. R.: Jour, of Exper. Medicine, Vol. II, pp. 233-313. 1897. 

2 Dixon: Jour, of Physiology, Vol. XXX., p. 97, 1903. 






DIGITALIS AS A DIURETIC 191 

spinal cords are very often accompanied by a marked increase in 
reflex movements. The same may be observed also on mammals, all 
showing an increase of the reactions of nerve centers under the in- 
fluence of the digitalis. Toxic doses of digitalis lead to convulsions 
which are undoubtedly of central origin. The direct therapeutic 
effect of digitalis on the cord and medullary portions of the nervous 
system is that of a general nerve tonic, especially on the vagus 
nucleus. 

8. Digitalis as a diuretic. — Any drug which produces so profound 
an influence on the circulatory system as digitalis may be expected 




Fig. 57. — The influence of digitalis on the irritability and muscle work of the gas- 
trocnemius of the frog. Tracing No. 1 is from 20 gram, frog, dose 8 minims of 
0.1 per rent, solution, allowing 20 minutes for absorption. There is little change in 
Irritability, but the amount of muscle work obtained is markedly diminished. Top 
tracing No. 2 shows the action of 6 minims of .0.1 per cent, solution on an 18-gram. 
frog after 15 minutes of absorption. The normal tracing is not shown, but it is very 
similar to the normal represented. Minute doses of digitalis slightly increase the 
amount of work given by the gastrocnemius. New tracing by La Force. 

to change the functional activity of the kidney. If for no other 
reason, this effect would occur indirectly from the action of the drug 
on the circulation. The volume of the circulation through the kidney 
is often decreased by profound vasoconstriction in the acute stage, 
but in the general administration of digitalis the total efficiency of 
renal circulation is raised. 

Digitalis produces diuresis. This can be demonstrated on the 
normal animal, where diuresis is distinct though relatively slight. In 
pathological conditions, especially when involving the circulatory ap- 



192 THE DIGITALIS GROUP 

paratus associated with dropsy and edema, this diuretic action is very 
greatly increased. 

The mechanism of diuresis by digitalis has been variously ex- 
plained, by some authors as wholly vascular, by others as due to a 
direct influence of the drug on the renal epithelium. While one must 
admit the favorable vascular effects it seems that one cannot deny 
the direct renal stimulation. In relation to the clinical dropsical 
condition there is a disturbance of function of the vascular endothe- 
lium over the body which varies the regulative control as between the 
fluids inside the blood-vessels and the fluids in the lymph spaces and 
in the tissues. Digitalis produces some stimulation of this endothelial 
tissue, increasing its efficiency of action. It thereby favors the taking 
up and elimination of the excess of tissue fluids. Similar action also 
falls on the lining cells of the renal blood-vessels as well as on the 
renal Epithelium. 

9. The local irritating effect of digitalis. — Digitalis applied 
locally to mucous membranes or hypodermically injected into the 
cutaneous or muscular tissues, produces considerable local irritation. 
This irritation may lead to the usual cycle of inflammatory changes, 
even to the formation of local abscess. There is a sharp stimulation 
of the sensory nerve endings, accompanied by acute pains. These 
facts make it undesirable to administer members of this series hypo- 
dermically. 

Digitalis, by way of the mouth, when its administration is oft 
repeated, has a tendency to produce gastric irritation and even 
inflammation. The nausea and vomiting that occasionally occur after 
digitalis, or more often after squills, are due to reflexes set up by 
gastric irritation. 

IV. 

The Cumulative Action of the Digitalis Series. 

The effects of digitalis are very persistent in the body. Absorption 
of the drug is indeed relatively slow, but its elimination is extremely 
slow, complete elimination taking place only after many days. The 
result is that in repeated dosage the effects are additive, i.e., cumu- 
lative. Cases of poisoning by digitalis have occurred from the too 
rapid administration of otherwise therapeutic doses. Digitoxin 
especially, which is the most toxic of the series, a dose of 2 mg. being 
dangerous for a grown man, is particularly slow in its elimination, 
hence cumulative in its action. 



SUMMARY OF PHARMACOLOGICAL ACTION 193 

The great variation in the strength of digitalis leaves and the 
preparations made therefrom, together with the fact that the active 
principles tend to decompose, all require standardization of these 
drugs by measurement of the reactions on mammals. At the present 
time most firms are issuing physiologically standardized preparations. 
The clinician should be particularly careful to use recently stand- 
ardized preparations, a caution that applies no less to the experi- 
mentalist. 

V. 

Summary of Pharmacological Action. 

The members of the digitalis series are extremely toxic, yet because 
of their almost specific action on the circulatory apparatus they have 
proven invaluable as therapeutic agencies. Members of the series 
vary somewhat in their relative intensity of action at different points 
of the body. In therapeutic quantity the chief changes produced 
in the body are: Strengthening of the heartbeat and slowing of its 
rate — strengthening through direct muscular action and slowing 
through stimulation of the inhibitory nerves, primarily through the 
inhibitory center in the medulla. There is a sharp and general 
rise of blood-pressure from arterial constriction, the effect being 
produced primarily by direct stimulation of the muscles of the 
arteries, but in some degree by similar stimulation of the vasomotor 
center. The arterial constriction is greatest in the splanchnic region, 
in mild doses being almost limited to this area. However, vasocon- 
striction is produced in all parts of the body, especially by the very 
toxic digitoxin. In toxic dose the inhibitory stimulation of the heart 
is profound, while the direct increase in muscular irritability tends 
to produce arrhythmia and delirium cordis. The algebraic sum of 
these two factors results in great irregularity of blood-pressure in 
this stage. 

The change in the circulation to some extent accounts for the 
diuretic value of digitalis, though a favorable stimulating effect 
upon the renal epithelium is to be assumed. Digitalis produces local 
irritation of the mucous membranes. Acute sensory stimulations, 
also inflammatory changes, occur in the local area when digitalis is 
given hypodermically. The inflammation is accompanied by the 
usual vascular congestion, edema, and sometimes degeneration of 
the tissue with pus formation. The sensory stimulations lead to im- 
portant reflex effects, also to acute pain. Local irritation in the 



194 THE DIGITALIS GROUP 

stomach produces nausea and vomiting. Toxic doses induce central 
nervous spasms ending in paralysis. 

The digitalis substances act cumulatively, due to their extremely 
slow elimination from the body. Excretion occurs chiefly through 
the kidney. In the present state of our knowledge of the chemistry 
of the active principles of this group clinicians must rely upon 
physiological standardization of these products. 



BUFONINB AND BUFOTALINE. 
I. 

Historical and Chemical. 

Faust 1 (1902) isolated and identified two digitalis-like principles from the 
skin of the common toad. It was known in ancient times that the dried skin 
of the toad possessed certain toxic properties and this material entered into the 
list of medicinal substances. Bufonine possesses the formula C 35 H540 2 , and 
bufotaline, C34H46O103. They are not glucosides but are chemically related to 
cholesterol. 

These substances are of peculiar interest because of their animal origin. 

II. 

Pharmacological Action. 

When injected subcutaneously or given by way of the mouth they produce 
digitalis-like changes in the functions of the animal tested. 

1. On the frog's heart. — Bufotaline produces on the frog's heart a marked 
slowing of the rate and an increase of the pulse volume. 

2. On the mammal. — Subcutaneously a 2.6 mgr. dose produced in the dog 
increased secretions and evidences of nausea followed by vomiting. There is a 
decrease in the rate and amplitude of respiration with Cheyne Stokes breathing. 
The heart is very irregular, the pulse small and strong. Similar phenomena occur 
in rabbits, but as the experiment proceeds there is a distinct dyspnea as with 
digitoxin. In the toxic stage convulsions occur. 

3. On blood-pressure and the pulse. — On mammals bufotaline produces 
a decrease in the pulse frequency with an increase in the pulse volume. 

Bufonine produces the same qualitative physiological effects as bufotaline, 
but is much weaker in its action. 

1 Faust, Edwin S.: Archiv f. Path. u. Pharm., Vol. XLVIL, p. 278. 1902. 



CHAPTER XXI. 
THE SAPONIN AND SAPOTOXIN GROUP. 

I. 

Historical and Chemical. 

Saponin and sapotoxin are widely distributed and highly toxic glucosidal 
principles. They are pharmacologically classified with the protoplasmic poisons, 
but are inserted here because chemically they are non-nitrogenous and in decom- 
position yield glucose. They are of the general chemical composition C n Han = eOio 
(Robert). 

Of the plants yielding members of the group may be mentioned as most 
important 

The Soapbark, Quillaja saponaria 
The Soapwort, Saponaria officinalis 
Sarsaparilla, Smilax 
The Corncockle, Agrostemma githago 

Closely related to the Saponins are the Solanins, which are glucosidal alka- 
loids yielded by the black nightshade, bitter sweet, potato, etc., members of the 
species Solanum. Solanin is decomposed into a glucose and a poisonous base, 
solanidin. Solanin is present in the green and growing parts of the potato, some- 
times in quantities sufficient to produce distinct poisonous symptoms. Saponin 
is very much less toxic than sapotoxin. 

II. 
Details of Pharmacological Action. 

Members of the saponin series are chiefly of toxicological interest. They 
are toxic to practically all the tissues. Their property of forming emulsions 
adapts them to commercial use to cleanse substances that are injured with the 
alkalies. For example, soapbark enjoys a well-merited popularity as a hair wash. 

i. Sapotoxin as an irritant. — Sapotoxin is a violent local irritant. When 
inhaled this action on the nasal epithelium leads to uncontrollable reflex 
sneezing. The local inflammation thus produced may under certain conditions 
prove decidedly injurious. 

Hypodermic injections also lead to inflammation at the point of injection. 

When introduced into the stomach sapotoxin produces the usual cycle of events 
following gastric irritation, namely, pain, nausea, and vomiting. As absorption 
does not readily occur systemic effects may not follow these local gastric changes. 

2. Toxic systemic effects. — The toxic symptoms produced by the sapo- 
toxins are in large part due to the irritant nature of the drug. There is in 

195 



196 



SAPONIN AND SAPOTOXIN GROUP 



the mild stages general malaise, loss of appetite, often with vomiting and 
diarrhea, feeble pulse, and respiration, leading in the stronger action to con- 
vulsions and respiratory failure. The tissues throughout the body show more 
or less evidence of inflammation and disintegration, especially the capillaries 
whose walls are often permeated, showing hemorrhagic extravasation. The 
hemoglobin is discharged from the blood by the hemolytic action of the saponins, 
a reaction which also takes place in the test tube. The explanation of the 
hemolysis is that the saponins dissolve the fat-like material in the wall of the 
corpuscle. 

3. Saponin. — Loeb and Wasteneys * have reported experiments showing that 
the cytolytic action of saponin on the cortical layer of the eggs of the sea urchin 
tends to increase the rate of oxidation under certain conditions. They give the 
following table as an example: 

TABLE I 



Eggs of S. Purpuratus, Temp. 15°C. 



Oxygen 
consumed 
per hour 



Coefficient of 

rate of 

oxidations. 



Unfertilized eggs 

The same eggs after cytolysis with saponin 

Unfertilized eggs 

The same eggs after cytolysis with saponin 



Mgr. 
0.15 
1.07 
0.22 

0.80 



1.00 
7.10 
1.00 
3.60 



" The variation in the effects of cytolysis in the two experiments may be due 
to the fact that in the second experiment an excessive amount of saponin was 
used. 

" This experiment proves that the increase in the rate of oxidations due to 
fertilization or artificial membrane formation is merely caused by the cytolysis 
of the cortical layer." 

4. Solanin. — The potato poison, solanin, has the same general toxic action 
as saponin and requires no special discussion. 



1 Loeb, J., and Wasteneys, H. : The Journal of Biological Chemistry, Vol. 
XIV., p. 479, 1913. 



F. Drugs, Chiefly Alkaloids That Primarily Influence 
General Metabolism. 

CHAPTER XXII. 

HYDROCYANIC ACID. 

I. 

Chemical. 

Hydrocyanic acid and the cyanides are very toxic substances 
which owe their physiological action to the CN group, cyanogen. 
This group is represented in nature in certain animal secretions and 
in certain plant products. It is present in the seed of the bitter 
almond in the compound known as amygdalin. When amygdalin is 
decomposed by the natural ferments it sets free hydrocyanic acid 
or prussic acid. The bitter almond kernel yields about one-fourth 
of one per cent, of hydrocyanic acid, according to the reaction: 

C 20 H 27 NO„ + 2H 2 = 2C 6 H 12 6 + HCN -f C 6 H 5 COH 

Amygdalin Dextrose Prussic Benzaldehyde 

acid 

The inorganic salts, the cyanides, in solution, yield the active 
cyanogen ions. The most common of the salts used in experimenta- 
tion and in medicine are sodium cyanide and potassium cyanide. 

II. 

Outline of Pharmacological Action. 

1. Toxic to protoplasm, especially to nervous tissue, which it 
paralyzes after an initial stimulation, the respiratory center being 
the vulnerable point. 

2. Destructive to enzyme action. 

III. 
Details of Pharmacological Action. 

i. On the central nervous system. — Prussic acid is especially 
toxic to animal tissues and particularly to the delicately sensitive 

197 



198 HYDROCYANIC ACID 

nerve tissues. Its toxicity is undoubtedly due to interference with 
oxidations, a deduction that is strengthened by the experiments of 
Loeb on general protoplasm. Loeb x has found that potassium cyanide 
inhibits the oxidation processes in the protoplasm of the ova of 
certain invertebrates. 

On nerve tissues of all kinds the cyanides at first increase the 
irritability, then depress and paralyze. Particularly on the centers 
of the medulla does this change show itself. These centers have their 
reflex irritability greatly increased at first, then rather quickly follows 
a marked depression to the point of complete loss of irritability. The 
cycle of changes is not unlike that of asphyxiation, a phenomenon 
that is indeed involved. The nervous centers controlling respiration, 
the glands, the eye, and the vascular mechanisms, are all at first 
stimulated then rapidly depressed, all in a few seconds in the presence 
of toxic doses. These changes are of themselves largely sufficient to 
explain the cycle of symptoms which occur on the administration of 
prussic acid and the cyanogen compounds. 

2. On respiration. — The action of the cyanides on the respiratory 
center is so striking and so important that it calls for special men- 
tion. Under the cyanide influence the discharges from the respiratory 
center are greatly strengthened and markedly accelerated. These 
changes are followed by respiratory depression to the point of com- 
plete standstill. The ganglion cells of the respiratory center are 
directly altered by the cyanides in such manner as to prevent the 
utilization of oxygen. In therapeutic quantity hydrocyanic acid is 
therefore a respiratory stimulant. Dresser 2 showed that 0.6 mgr. 
potassium cyanide produced in the rabbit both an acceleration of 
respiratory rate and an increase in the expiratory volume. His ex- 
periment is as follows: 



Rabbit (weight 2170 grs., under 1.6 grms. urethan, vagi sectioned). 




Expiratory 
volume. 


Frequency per 
minute. 


Normal 


156 cc. 
175 cc. 


30 


After 0006 grm. KCN 


32 







In toxic quantity, and cyanogen is very toxic, it quickly leads to 
loss of medullary respiratory control, and death follows from 

x Loeb, Jacques: Biochemische Zeitschrift, Vol. XXVI., p. 279, 1910. 
2 Dresser, H.: Archiv f. Exper. Pathol, u. Pharmakol, Vol. XXVI., p. 237, 
1890. 



ACTION ON THE CIRCULATORY SYSTEM 199 

asphyxiation of the tissue. The stage of depression can be greatly 
alleviated and sometimes recovered from by artificial respiration, since 
the tissues are not directly so strongly influenced toxicologically as 
are the nervous reflexes involved. 

3. On the circulatory system. — Changes occur in the circulation 
at three points, i.e., the peripheral blood-vessels, in. the heart, and 
in the controlling nerve centers. Using isolated organs (the kidney) 
Sollmann has shown a vascular dilation when solutions of hydrocyanic 
acid gas were perfused. When the normal solutions were substituted 
there was a disappearance of the dilation of the blood-vessels. 

The heart is directly influenced by this drug. Loewi 1 has 
shown that .00013 per cent, hydrocyanic acid is sufficient to partially 
depress the pulse frequency, while .00025 per cent, rapidly lowers the 
amplitude of contraction. Prolonged contact of the cyanides is espe- 
cially depressing to the heart function, presumably by interference 
with the oxidation processes. 

The chief cardiac change, however, is due to the influence of the 
cyanides on the central nervous system. The vagus center is at 
first stimulated, leading to cardiac slowing by vagus inhibition. In a 
similar manner the vasomotor center shows an initial stage of in- 
creased tone, followed by depression of function as toxicity appears. 

When perfused through the isolated frog's heart hydrocyanic 
acid or its compounds quickly produces a cessation of the rhythm, 
the heart stopping in diastole. The irritability of heart muscle, al- 
though depressed, is not completely lost for a time, as can be proven 
by applying stimulating electrodes directly to the muscle. Recovery 
with the perfusion of normal fluids is relatively rapid. 

4. On metabolism. — It is evident that a substance so toxic as 
a cyanide will influence the metabolism of protoplasm in general. 
This is true in this case. The CN group, by interfering with oxida- 
tions, depresses metabolism. This is proven by experiments on both 
animals and plants. Animals show a decrease in the percentage of 
oxygen consumed and carbon dioxide liberated, further proof indicat- 
ing a decrease in the oxidative processes (Geppert). 

There is some evidence that the cyanides take part in the reactions 
occurring in certain normal functions of the tissue. One such evi- 
dence is found in the presence of sulpho-cyanides in the saliva. Then, 
too, prussic acid is eliminated from the body in the form of sulpho- 
cyanides. 

Prussic acid produces cyan-methemoglobin in the body, a reac- 
1 Loewi, Otto: Archiv f. Pathol, u. Pharm., Vol. XXXVIIL, p. 126, 1897. 



200 HYDROCYANIC ACID 

tion that is especially characteristic when the reagent is mixed with 
blood in the test tube. This compound is a combination between the 
hematin and the hydrocyanic acid. In cases of poisoning from this 
drug the blood of the animal possesses a bright red color, which is 
characteristic. The reaction between methemoglobin and hydrocyanic 
acid is characteristic and extremely sensitive. If a sample of blood 
have added potassium chlorate to produce methemoglobin, and a 
drop of this fluid be allowed to spread on a filter paper, then the 
merest trace of hydrocyanic acid in a suspected solution when added 
to this methemoglobin paper will produce a change in color from the 
dark brown-red to a brilliant scarlet-red. 



CHAPTER XXIII. 
ACONITE. 

I. 

Historical and Chemical. 

Aconite, from the roots of monkshood, Aconitum napellus, is one 
of the most toxic, and at the same time one of the oldest known 
poisons. The active alkaloid, aconitine, presents some difficulties in 
its isolation because of the readiness with which it decomposes. The 
related alkaloids of this group are found in species of the genus 
Aconitum, from which are derived aconitine, with the chemical 
formula, Cs^^NO^ ; pseudoaconitine, C 36 H 49 N0 12 ; delphinine, 
CgjH^NO,.. 1 The last named drug is less toxic than the first. 

On hydration aconitine and its relatives break down into acetic 
acid and benzaconine. The latter further decomposes into aconine 
and benzoic acid. Because of the ease of cleavage of aconitine there 
is in its commercial preparations great variation in the propor- 
tion of the different cleavage products. This presents an element of 
danger, as is obvious, considering the toxicity of the alkaloid, the 
fatal dose for man being 3 mgr. 

II. 

Outline of Pharmacological Action. 

1. Aconite is a general protoplasmic poison of extreme toxicity. 

2. Like many poisons, it at first stimulates, then paralyzes the 
tissue. Aconite is particularly poisonous to the basic centers of the 
central nervous system. 

3. It produces primary sensory stimulation followed by paralysis. 

4. The blood-pressure is depressed by vasodilation and by slowing 
of the heart through primary stimulation of the vagus center. 

5. Heart muscle, as such, is stimulated, and is finally set into 
fibrillation by toxic doses. 

1 These formulae are those presented by Schmiedeberg's Pharmakologie, 6th 
edition. 

201 



202 ACONITE 



III. 

Details of Pharmacological Action. 

i. Systemic action. — Aconite in toxic quantity, 2 or 3 mgr. for 
man, produces almost immediate paralysis of the medullary centers, 
with respiratory and cardiac failure. In therapeutic quantities 
there is a primary medullary stimulation of the cardiac inhibitory 
center (questioned by Mackenzie recently), but with depression of 
the respiratory mechanism. The sensory symptoms are also most 
characteristic. After absorption there is a stinging, prickling, or 
tingling sensation of the skin. If the drug is taken by the mouth, this 
local effect appears first in the mouth, tongue, and throat. If these 
first symptoms are rather severe they are apt to be followed by a 
feeling of numbness from incipient local sensory paralysis. Aconite 
is rather readily absorbed, and when applied locally to the skin or to 
mucous surfaces it leads to the same local sensory symptoms as 
when taken internally. Stimulation by local action produces marked 
reflexes which influence the different fundamental tissues accord- 
ing to the point at which the local stimulation is produced, i.e., in- 
salivation, gastric irritation, with nausea and ofttimes vomiting. 

The fact that the peripheral sensory effects are produced by aconite 
after absorption, is generally explained on the ground that the stimu- 
lation and paralysis occur in the peripheral structures. Aconite 
apparently produces a somewhat selective paralysis of cutaneous 
sensory mechanisms. 

2. Aconite on the central nervous system. — The primary action 
of aconite on the central nervous system is that of mild initial stimu- 
lation, followed by depression and paralysis. This is true especially 
for the medullary and spinal centers. Slight, if any, effect is noted on 
the cortical region, since consciousness remains intact until death. 
Of the medullary centers the chief symptoms of stimulation are 
noted in connection with the cardiac inhibitory center and the vaso- 
motor center. The cardiac inhibitory center is primarily stimulated, 
as shown by slowing of the heartbeat. In the same way the vaso- 
motor stimulation is indicated by peripheral vascular constriction. 
The respiratory center is mildly stimulated, then the amplitude is de- 
pressed and the movements slowed, a condition which is succeeded 
by ultimate paralysis and death by asphyxiation. 

3. Aconite on the circulatory system. — The circulatory influences 
of aconite are twofold, i.e., cardiac and vasomotor. "When the drug 



ACONITE ON THE CIRCULATORY SYSTEM 



203 



is injected intravenously into the circulatory apparatus of a normal 
animal, for example, a frog or a mammal, the heart is at first ac- 
celerated, then greatly slowed, often stopped. Still later this is fol- 
lowed by a series of weak beats or sometimes by complete quiet. 
This contradictory picture is explained by the successive stimulations, 
which occur on different parts of the cardiac mechanism. The stimu- 




FiG. 58. — The stimulating action of .001 per cent, aconite on the contractions of 
the frog's heart. This concentration ultimately leads to arrhythmia, but the imme- 
diate effect is a great increase in the contraction. A, first perfusion ; B, second perfu- 
jion after several minutes' interval. Time in seconds. 



lating effects of the aconite fall on the medullary centers, the nerve 
endings in the muscle, and on the muscle itself. In the first or ac- 
celeration stage the accelerator nerve endings are dominant; in the 
stage of slowing and inhibition the inhibitory nervous apparatus is 
dominant. After the regulative nerves are finally paralyzed the 
fundamental rhythmic property of the muscle is free to act, and the 
heart is able to carry on beats for a time. The automatic rhythm 
finally ceases. However, the muscle can still be made to contract 
by direct electrical stimulation, though this power does not last 
long. 

The direct action of aconite on isolated cardiac muscle is primarily 
stimulating, producing an increase in the rhythm, followed by in- 
coordination and later by paralysis. When the rhythm has disap- 
peared, the muscle can be made to contract by the direct application 
of a strong electrical stimulus. Cushny x has recently examined the 

1 Cushny, Arthur R. : "The Irregularities of the Mammalian Heart Observed 
under Aconitine and on Electrical Stimulation," Heart, Vol. I., pp. 1-22, 1909. 



204 ACONITE 

reactions of the mammalian heart and finds that there is marked 
interference, both with the conduction of the contraction wave and 
with the rhythm. The mammalian heart in an early toxic stage 
shows in a large percentage of the cases reversal of sequence, i.e., to 
the ventricle-auricle rhythm, in which the impulse is " generated in 
the ventricle and spreads upward to the auricle." He finds an im- 
paired conduction, which may at times lead to partial or complete 
block. There is also a tendency to " sudden changes in the rhythm 
of the whole heart. It is evident that aconite produces a profound 
change, not only in contractility, but in rhythm and conductivity in 
the mammalian heart.' ' 

4. Aconite on the blood-vessels. — The exhibition of aconite 
causes an initial contraction of the blood-vessels, from the stimulating 
action of the drug on the vasomotor center. This stage of stimulation, 
however, is very brief, and later, as the nerve center becomes depressed 
vasodilations occur, as shown by slight flushing of the skin. In the 
therapeutic action of aconite on the circulatory system, therefore, 
the great inhibitory slowing of the heart, together with the tendency 
to vascular dilation, leads to a general fall of blood-pressure, with 
depression of the circulation as a whole, a condition which undoubt- 
edly enters into the antipyretic action of the drug. 

5. On the glands. — An increase in the secretion of the glands of 
the mouth and especially of the skin is noted after aconite. But the 
increased flow of saliva is primarily reflex, due to stimulation of 
sensory endings in the mouth. However, some stimulation of the 
secretory center in the medulla may also occur. 

6. Aconite as an antipyretic. — Aconite because of its great toxic- 
ity to protoplasm tends to lower the metabolic processes of the body. 
In fevers, which result from increased central stimulation, aconite is 
particularly effective, and lowers the temperature by depressing 
metabolism. The lowering of heat production is added to the in^ 
creased heat loss from the dilation of the cutaneous blood-vessels 
and the increased secretion of perspiration mentioned above, hence 
the general body temperature is brought down. To what extent this 
action falls on the heat regulating centers of the brain is not fully 
explained. 



SUMMARY OF PHARMACOLOGICAL ACTION 205 

IV. 

Summary of Pharmacological Action. 

Aconite is the most toxic of alkaloids and is poisonous to all the 
tissues of the body. Its action is characterized by an initial irrita- 
tive or stimulative process, followed by loss of function or by paraly- 
sis. In the central nervous system the cortex is not particularly 
affected, but the vital centers of the brain-stem and cord are es- 
pecially poisoned. The cardiac inhibitory, the vasomotor, and the 
secretory centers of the medulla are initially stimulated, then with 
the respiratory center, depressed and paralyzed. Of these influences 
the stimulation of the respiration is practically negligible, while that 
of the inhibitory center is strong. Death follows from the cessation of 
respiration and by paralysis of the heart. 

The most characteristic, one might almost say specific, influence 
of aconite is on the sensory receptive organs. Cutaneous sense organs 
are stimulated by the smaller doses, which may reach them either 
locally or through the circulation. Here, too, stimulation is followed 
by depression and paralysis. On peripheral tissues, the glands, 
skeletal muscles, heart muscle, and smooth muscle, aconite exerts a 
rather strong initial stimulation, though in each tissue ultimate 
paralysis follows. 

The general effect on metabolism is to lower heat production. 
Dilation of the blood-vessels of the skin and the greater evaporation 
of sweat increase heat dissipation, hence contribute to the general 
lowering of temperature. The former use of aconite as an antifebric 
is falling into disrepute because of the danger from its depressant 
cardiac action. Aconite is being displaced by safer antipyretics which 
are now available. 



CHAPTER XXIV. 
VEEATRINE. 

I. 

Historical and Chemical. 

Veratrine is representative of a series of very toxic alkaloids 
closely related to aconite and derived from different species of 
Lilaceae. The most important is veratrine, C 32 H 49 N0 9 , from Veratrum 
sabadilla and Veratrum viride, and protoveratrine, C 32 H 51 N0 11 , from 
Veratrum album. 

Aside from these there are some eight or ten related alkaloids 
which have been isolated and most of them tested pharmacologically. 

The name Hellebore, sometimes used, confuses the above plants 
with Helleborus niger. Helleborine, the active principle of the latter 
plant, is classified in the digitalis series, to which it is most closely 
related. The alkaloid of the death Camas, the poisonous lily of the 
valleys of the Cascade Mountains, contains members of this series, as 
demonstrated by Slade 1 in 1905. 

II. 

Outline of Pharmacological Action. 

1. The chief action of the veratrine alkaloids is due to their ex- 
treme general toxicity, but they possess a degree of selective activity 
on sense organs and sensory nerves cmd on muscle substance. 

2. A peculiar and typical stimulation of muscular contraction 
leads to persistence of the muscular tone and delayed relaxation. 

III. 

Details of Pharmacological Action. 

i. Veratrine on sensory and nervous mechanisms. — Like aco- 
nite, veratrine causes a pronounced stimulation of sensory organs, 
especially the cutaneous sense organs. This occurs whether the drug 
be taken systemically or brought into contact with the tissues locally. 
The symptoms are smarting and tingling, and peculiar temperature- 

1 Slade: American Journal of Pharmacy, Vol. LXXVIL, p. 262, 1905. 



VERATRINE ON SKELETAL MUSCLE 207 

like sensations, followed by anesthesia of the skin. On the nasal 
mucous membrane it leads to irritation, with reflex stimulation, sneez- 
ing, coughing, etc. In the mouth the sensations are those of burning 
and stinging pain, with slight involvement of taste sensations. All 
of these symptoms are followed by anesthesia in the later stage of 
action. 

Yeratrine is extremely toxic to nerve tissues. Yet under certain 
conditions of hyperirritability of these systems veratrine is truly 
antidotal. 

2. Veratrine on skeletal muscle. — Pharmacologically the action 
of veratrine on skeletal muscle is most interesting. All kinds of 
muscular tissues are affected by the alkaloid, and in much the same 
way in the various species of animals. 

Isolated skeletal muscle contracts in the normal way after verat- 
rine, but relaxation is extraordinarily prolonged, many times that of 
the normal relaxation. This effect is characteristic. When the 
poison is given systemically the inability of the skeletal muscles to 
quickly relax leads to a peculiar type of general muscular movement 
in the poisoned animal. Such animals can make quick enough mus- 
cular contractions, as in the limb extensions in leaping, but the 
return to the normal relaxed position is hindered. This leads to 
very irregular and seemingly incoordinated movements, and to the 
fixing of the body in the position of contraction of the stronger 
sets of muscles. 

The explanation offered of this veratrine effect, which has re- 
ceived most general consideration, is that of Bottazzi. 1 This author, 
in 1901, called attention to the double nature of skeletal muscle sub- 
stance, namely, that it possesses highly differentiated fibrillae sur- 
rounded by a certain amount of less differentiated sarcoplasm. The 
fibrillae are responsible for the characteristic quick contractions of 
skeletal muscle, in which the part taken by the sarcoplasm is slight 
and thrown into the background. Under the influence of veratrine 
(and the effect is produced by other muscle poisons, such as muscarine, 
helleborine, etc.), the irritability of the sarcoplasm is sharply raised. 
When a muscle receives a single stimulus, such as calls forth a typical 
simple contraction, the fibrillae respond with the usual rapidity, and 
the contraction phase is as short and abrupt as in the normal. Ke- 
laxation begins in the usual way, but before it proceeds far is arrested 
by the slowly developed second contraction, and is followed by a 
very prolonged relaxation. The delayed relaxation is by this view 
1 Bottazzi: Arch. f. Physiologie, p. 377, 1901. 



208 



VERATRINE 






due to the stronger contraction of the slower reacting sarcoplasm, 
which develops under the influence of veratrine. The recorded trac- 
ing is the algebraic sum of the contractions of the two substances, 
i.e., the quick contraction of the fibrillar and the slower but hyper- 
stimulated contraction of the sarcoplasm. 

By the above theory it is obvious that the prolongation effect will 
be greater in those tissues which have relatively greater amounts oi; 
sarcoplasm. This is found to be the case. The effect is more pro- 
nounced in the order — smooth, cardiac, skeletal muscle. Certain ani- 
mals whose muscles of a given type are known to possess a relatively 




Fig. 59. — The influence of veratrine, 0.0002 per cent, in Ringer-blood perfused 
through the coronary vessels of the cat heart, between the two arrows. There is a 
Blight delay in the effect represented by the time the fluid is flowing through the 
cannula. Just before the second arrow, the lever misses at the top an amount indicated 
by the dotted line. New tracing by Bullard and Stine. 



greater amount of sarcoplasm respond even more characteristically, 
as, for example, in the muscular tissues of the toad. 

3. Veratrine on the heart muscle. — Heart muscle, as has already 
been stated, is influenced by .veratrine in that the contractions are 
also prolonged and the relaxations delayed, a phenomenon shown most 
typically in the cold-blooded animals. The heart muscle tends to 
persist in a continuous contraction in the systolic phase. The heart of 
the mammal is similarly influenced, though the picture is compli- 
cated by a primary stimulation of the nerve fibers of the inhibitory 
apparatus. Even in the isolated mammalian heart this later stimula- 
tion produces a slowing at the beginning of the veratrine action. 



ACTION ON SMOOTH MUSCLE 209 

4. On smooth muscle. — Smooth muscle is strongly stimulated 
by veratrine, leading to increase in tone, with persistent contractions 
in organs where this type of muscle is dominant, i.e., the alimentary 
canal, the uro-genital system, the peripheral blood-vessels, etc. 

Yeratrine, like aconite, is a dangerously toxic drug. The thera- 
peutic effects, for which it was formerly used, are now produced more 
safely by other less toxic substances, hence the practical use of verat- 
rine has declined. It serves, however, through its muscular effects as 
one of our best pharmacological illustrations of characteristic and 
specific acting drugs. 



CHAPTER XXV. 
COLCHICINE. 

I. 

Historical and Chemical. 

Preparations of Colchicum autumnale have enjoyed a certain 
amount of popularity in the treatment of gout, though such treat- 
ment has not been based on any pharmacologically demonstrated ac- 
tivities. This plant yields two alkaloids, colchicine, C 22 H 25 N0 6 , and 
colchicein, C 21 H 25 N0 6 . 

II. 
Details of Pharmacological Action. 

i. General systemic and toxic effects. — Colchicine when given 
in therapeutic quantity produces little or no acute effects, but in 
stronger dose symptoms follow similar to those of aconite, and to 
some extent of pilocarpine. There is a slight increase in glandular 
and muscular activity, with evidences of sense-organ stimulation. 
These reactions are followed rather late by marked disturbances of 
the alimentary tract associated with violent pains, vomiting, and 
diarrhea. Continued therapeutic use leads to gastro-intestinal dis- 
turbance. Death is due to collapse of the respiratory system. 

The delay in the reaction of the body to colchicine is due to the 
fact that the real poisonous effects come only after oxidation of the 
alkaloid into an oxy-produce. 

2. Colchicine on the white blood corpuscles. — An action which 
should be mentioned and which can readily be experimentally dem- 
onstrated is the production by colchicine of a marked leucocytosis. 
The immediate effect is a decrease in the number of leucocytes, chiefly 
polymorphs in the blood stream. This acute effect is followed later 
by a marked increase. It would seem as though the alkaloid w* 
sharply stimulative to this more undifferentiated cellular type. Ii 
leucocytes are stimulated then in all probability the endothelial 

210 



ACTION ON WHITE BLOOD CORPUSCLES 211 

lymphoid, and synovial tissues, and the relatively undifferentiated 
connective tissues are also similarly stimulated. The stimulation of 
such tissues finds expression in cell growth and cell multiplication. 
However, and probably more important clinically, all such tissues 
as the endothelial tissues of the blood-vessels in reacting to stimula- 
tive agencies display first of all an increase in tonic resistance, a 
strengthening of the factors of control as displayed in their influence 
on osmotic and exudative processes. One must remember that such 
tissues form the boundary walls of cavities filled with fluids. It is 
suggested that this may be the explanation of the beneficial effect 
observed in the clinical use of colchicum in rheumatism, gout, etc. 



CHAPTER XXVI. 

EMETINE. 

I. 
Historical and Chemical. 

Emetine, C 14 H 18 CH 3 N0 2 , derived from the root of Cephaelis 
Ipecacuanha, is noted for its action as an expectorant and emetic. 

This alkaloid, too, is a general protoplasmic toxic substance and is 
to be classed with the aconite group. 

II. 
Details of Pharmacological Action. 

i. Systemic actions. — Emetine differs slightly from the other 
members of the group in its excessive toxic and local irritation. It 
is this property which, upon its administration, leads to marked 
irritation and stimulation of the mucous membrane of the mouth, 
throat, and stomach. In this way it quickly produces reflex nausea, 
with vomiting, and the train of associated symptoms. 

Ipecacuanha, as an expectorant and emetic, possesses the same 
dangers as have already been strongly emphasized in association with 
the other members of this series. 



212 



G. Drugs Poisonous to General Protoplasm. 



CHAPTER XXVII. 



COCAINE. 



I. 



Historical and Chemical. 

The tree Erythroxylon coca is native to the Andes of the west- 
ern coast of South America. The natives conducting the pack trains 
going through the mountain passes, chew the leaves of this species, 
in lieu of food, on their long mountain marches. They are said to 
go for extra long periods without rest or food under these conditions, 
endurance being greatly increased by the action of the active prin- 
ciple of the Coca leaves, cocaine. Cocaine was made known by 
Niemann, but its present popularity arose only after its introduction 
into use as a general local anesthetic in 1884 by Koller. Chemically 
cocaine is an alkaloid with the composition C 17 H 21 N0 4 . It is a 
methyl-benzo-ecgonine compound decomposing into ecgonine, pyri- 
dine, and benzoic acid. 



H 9 C- 



H 2 C- 



-CH CH 2 

I I 

N.CH 3 CH.OH 

I I 

-CH CH 2 

Tropine 



H 2 C CH CH.COOH 

I I 

N.CH, CH.OH 

H Q C CH CH 2 

Ecgonine 



H 2 C CH CH.COO.CH3 

I I 

N.CH3 CH.O.CO.CeH; 

I I 

H 2 C CH CH 2 

Cocaine 



Ecgonine has a close relationship to tropine which is a hydro- 
lytic cleavage product of atropine. The anesthetic action of cocaine 
is lost by the removal of the methyl group or of the acid radicle. 
Other alkaloids are present in small quantities in the species of this 
genus. These alkaloids owe their toxicity and action to the same 
base, ecgonine, but differ somewhat in the attached acid radicles. 

213 






214 COCAINE 

The most important of these alkaloids is tropacocaine, extracted from 
the Java Coca. 

II. 

Outline of Pharmacological Action. 

Cocaine is described as a general protoplasmic poison. Its action 
may be summarized as follows: 

1. Initial stimulation with later anesthesia of nerve tissues. Sen- 
sory nerves and sensory nerve endings are peculiarly susceptible. 

2. Local applications lead to local anesthesia, an effect which 
readily passes away when the concentration of the drug is suffi- 
ciently reduced by diffusion or absorption. 

3. The central nervous system is at first stimulated, then para- 
lyzed, chiefly in the descending direction. 

4. Stimulation followed by paralysis of the heart muscle. 

5. Marked vasoconstriction by central vasomotor stimulation and 
by peripheral stimtdation of the muscles of the blood-vessels. 

6. Increase in the muscular power and endurance of the skeletal 
muscle by direct action on the muscle fibers. 

7 . Marked mydriasis. 

III. 

Details of Pharmacological Action. 

i. On the central nervous system. — Cocaine is a recognized ex- 
citant of the cerebral cortex and the central nervous system. The 
excitement stage is associated with increased excitability of the cortex 
accompanied by restlessness, often passing into convulsions in the 
toxic stage, and ultimately ending in paralysis. The medullary cen- 
ters are excited, then depressed, shown in the quicker respiration, the 
slower heartbeat due to central vagus stimulation, and an increase 
in tone of the vasomotor center. All these stages pass rapidly into 
depression and paralysis. The spinal cord, after cocaine, likewise 
exhibits an increase in the irritability of the motor side of that 
apparatus. Reflexes are therefore increased, and this is true, not 
only for the cord reflexes, but for those reflexes which take place 
through the brain-stem, and even through the cortex itself. The 
change in function is due to an increase in the sensitiveness of the 
nervous elements. Dixon has determined that the amount of cocaine 
necessary to produce convulsions in the different species of animals 



COCAINE ON THE CIRCULATORY SYSTEM 



215 



closely corresponds to the proportional amount of brain matter per 
kilo, as indicated in the following table : 



Grams of brain 
per kilo of ani- 
mal. 



Rabbit. . . . 
Guinea-pig 

Pigeon 

Dog 

Ape 




Dose of cocaine 
per kilo neces- 
sary to produce 
convulsion. 



0.18 
0.07 
0.06 
0.02 
0.012 



Ott found also a strongly toxic influence on the posterior columns of 
the cord, indicating a slight degree of differential action within the 
cordu 

2. Cocaine on the circulatory system. — The initial effect of 
cocaine when injected into the circulation is a rise of blood-pressure. 




Fig. 60. — The recovery phase of the frog's heart from the depressing action of 
cocaine. New tracing by Kruse. 



This rise is due primarily to great vasomotor constriction, but in 
part to direct heart effects. The initial rise of pressure is generally 
followed by a rather sudden fall with a second rise as toxicity ap- 
proaches. In the toxic stages blood-pressure falls and the animal 
becomes markedly cyanotic. The variations in blood-pressure may 
be analyzed by considering the action of the drug on the different 
parts of the mechanism. 

3. The peripheral blood-vessels. — The most striking influence 
of cocaine is expressed in vasoconstriction. This is sharp, vigorous, 
and prolonged. The primary rise of blood-pressure is undoubtedly 
due to the stimulation of the vasomotor center in the medulla. There 



216 COCAINE 

is, however, a marked vasoconstriction both in the spinal animal, and 
in organs for which the vasoconstrictor nerves are severed. Hence 
the cocaine effect is peripheral as well as central. The peripheral 
effects are due in part only to stimulation of the nerve endings. 
Evidence in this direction is the fact that when there is a sharp 
rise of blood-pressure under the influence of cocaine injection, cutting 
the splanchnic nerves leads to a decrease of the pressure. The 
stronger solutions certainly stimulate the muscles of the blood-vessel 
walls directly, as observed in the blanching of the gums when cocaine 
is injected for dental purposes. 

4. Cocaine on the heart. — The intravenous injection of mild 
doses of cocaine leads to a marked slowing of the heart, occasionally 
after a short initial acceleration. This slowing is produced by the 
stimulation of the inhibitory center in the medulla. Cocaine per- 
fused through the isolated heart of the frog produces little change 
in rate, but a marked increase in the amplitude of contractions. This 
indicates a direct stimulation of the contraction amplitude of the 
cardiac muscle substance. This fact is further confirmed by the 
influence of cocaine on isolated terrapin heart strips in which also 
there is a marked increase in amplitude. The isolated mammalian 
heart gives evidence of direct stimulation of the heart by cocaine 
in therapeutic concentration, i.e., under 0.0002 per cent, concentration 
in perfusion fluids. 

In all heart work, whether it be muscle or nerve involved, the 
toxic end effect of cocaine is paralysis and loss of function. 

5. Cocaine on skeletal muscle. — As is shown by the practice of 
the South American natives, cocaine increases the efficiency of the 
neuro-muscular apparatus in the production of voluntary muscular 
work. Especially does this effect follow under conditions of fatigue 
and partial exhaustion. 

An analysis of this effect would lead one to suspect that it was 
due, primarily, to the heightened irritability of the motor nervous 
mechanism. Experiments on the irritability of the spinal cord indi- 
cate that this is a factor. When the isolated gastrocnemius muscle 
contracting under repeated electrical stimulation is under the influ- 
ence of cocaine the amount of energy expended is much greater and 
the onset of muscular fatigue is strikingly delayed. Both these effects 
in this experiment are to be attributed to the direct action of cocaine 
on skeletal muscle substance. The functional influence is indeed 
quite similar to that on cardiac muscle. It is this double favorable 
therapeutic influence of cocaine on the nerve and on the muscle which 



COCAINE ON THE EYE 217 

leads to the feeling of freshness and strength under its influence. It 
is a strong factor in the formation of the cocaine habit. 

6. Cocaine on the eye. — One of the toxic symptoms of the in- 
fluence of cocaine is the dilation of the pupil of the eye. This effect 
is best studied by the direct application of cocaine into the eye. 
This leads to dilation of the pupil and a partial loss of accommodation. 
The dilation of the pupil is not associated with the loss of the light 
reflex. In other words the oculo-motor nerve is still reflexly active 




Fig. 61. — Showing the action of cocaine on the amplitude of contraction and the 
amount of work done by skeletal muscle. The lower tracing represents the work of 
the normal gastrocnemius of the frog ; the upper tracing, the cocainized muscle. Direct 
muscle irritability tested in the beginning of the experiment, the cocainized muscle 
showing very slightly greater irritability. Four minims of 0.5 per cent, cocaine was 
injected into the lymph sack 10 minutes before the experiment. Parallel experiments 
In which the cocaine acts for a longer time show depression on muscle contractility. 
New tracing by La Force. 

in the presence of the local mydriasis. Direct stimulation of this 
nerve produces active constriction of the pupil. When the superior 
cervical ganglion is removed cocaine still produces dilation. If, 
however, the post-ganglionic fibers, Figure 27, page 114, first be allowed 
to degenerate then the dilation is slight or absent. The whole effect 
is like that produced normally by stimulation of the cervical sym- 
pathetic and is to be attributed chiefly to stimulation of the endings 
of the post-ganglionic fibers on the radial muscles of the iris. 

7. The elimination of cocaine. — Cocaine, like alcohol, is prac- 
tically all consumed in the body. Not only is it oxidized, but the 
cleavage products, ecgonine, benzoic acid, etc., are oxidized. 

8. Local and anesthetic action of cocaine. — Cocaine owes its 
present therapeutic position primarily to the fact which was first 
emphasized by Koller in 1884. This action is dependent upon the 
fact that when cocaine is brought in contact with the tissues in 
sufficient concentration it leads to a temporary narcosis of all nerve 



218 COCAINE 

structures, especially of sensory nerve endings. This analgesic effect 
comes on after five or ten minutes, lasts for a variable time, accord- 
ing to the rapidity with which absorption takes place from the local 
area, and gradually and completely disappears. 

Cocaine is, therefore, admirably adapted to local and minor 
operations. When injected into the tissues by hypodermic syringe 
or applied locally as in the case of mucous membranes, the eye, etc., 
it produces a local anemia from its stimulation of the small blood- 
vessel walls, also a local analgesia. Solutions of from 0.5 (or weaker) 
to 2 per cent, are used for this purpose. In every case rapidity of 
absorption is hindered as far as possible and care must be taken 
never to allow a maximum dose of more than 50 mg. to be absorbed 
into the general circulation. Susceptibility varies extremely with 
different individuals, many are more tolerant, but one grain (66 mg.) 
is often a toxic dose. With deep analgesia not only are the local 
sensory endings narcotized but nerve trunks can be cut without pain. 
For larger nerve trunks it is necessary, however, to inject the cocaine 
directly into the nerve sheath. 

Cocaine is also used for major operations by the method of spinal 
analgesia. For this purpose cocaine is injected directly into the 
meninges around the spinal cord, the puncture being made between 
the laminae of the lumbar vertebrae. As the drug diffuses around the 
meninges of the spinal cord it produces a temporary spinal paralysis 
and this persists long enough for elaborate and extensive surgical 
operations. The first major operation of this type was executed 
by Bier in 1898, the operation being the resection of a tubercular 
foot under spinal analgesia produced by 3 cubic centimeters of a 
0.5 per cent, solution of cocaine. 1 The limit of the spinal use of 
cocaine is set by the presence of the nerves of vital function having 
their origin from the cervical cord. Of course spinal analgesia cannot 
safely be carried to the cervical region, since the loss of function of 
the phrenic nerves, arising from the third and fourth spinal nerves, 
will lead to respiratory paralysis. 

9. The cocaine habit. — The use of cocaine, like alcohol, mor- 
phine, etc., leads to the formation of the habit. Under the cocaine 
habit the individual has an irresistible craving for the drug. The 
body becomes more and more tolerant, therefore correspondingly 
stronger doses are required to produce the desired stimulations. 

1 Murphy, John B.: "Analgesia from Spinal Subarachnoidean Cocainization," 
Jour, of Am. Med. Association, Vol. XXXVI., p. 359, 1901. 



SUBSTANCES SIMILAR TO COCAINE 219 

Cocaine is very much abused, especially in America, where it is said to 
have reached a widespread use among the negro population, as well 
as among the whites. 



IV. 

Substances Which Produce Anesthesia Similar to Cocaine. 

The cocaine nucleus permits chemically of a number of substitu- 
tion products, and a knowledge of the factor which contributes to the 
anesthetic properties has led to the development of a long series of 
compounds of this group. 

In the development of these compounds the attempt has been 
made to produce drugs which increased the anesthetic effects and 
as far as possible diminish the undesirable and toxic effects of cocaine. 
Of these synthetic and substitution products the most important, 
together with their variations from the cocaine reaction, are as 
follows : 

Tropacocaine. This synthetic alkaloid produces effects very similar 
to cocaine. The main differences are that it acts more rapidly, pro- 
duces little or no dilation of the pupil and less vasoconstriction. Its 
anesthetic power is slightly greater than cocaine, and it is somewhat 
less poisonous. 

Eucaine. Two synthetic eucaines with an ecgonine foundation 
have been produced, a Eucaine (C 19 H 27 N0 4 ) was the first produced 
and used, but it has been abandoned because of its marked irritant 
action. /? Eucaine (C 15 H 21 N0 2 ) enjoys a certain amount of popu- 
larity because of its lessened toxicity, one-fifth as toxic as cocaine. It 
produces neither vasoconstriction nor mydriasis. It is slightly less 
stimulating to the central nervous system and has a less tendency to 
produce convulsions than does cocaine. It does not decompose on 
prolonged boiling as does cocaine. 

Stovaine produces a similar local anesthesia to cocaine. It has 
the advantage in that it is more soluble and less toxic. 

For hypodermic and intramuscular injections it has the very great 
advantage in that it can be sterilized without decomposition. It 
leads to vasodilation rather than to the constrictor spasms which 
characterize cocaine. 

Holocaine is a coal tar product, produced by the interaction of 
phenacetine and paraphenetidine. It is more poisonous than cocaine, 
produces quicker anesthesia without vasoconstriction, has some anti- 



220 COCAINE 

septic action, and the effect passes away in a shorter time than with 
cocaine. 

Novocaine is p-aminobenzoyldiethylaminoethane hydrochloride, 
with the formula CH 2 (C 6 H 4 NH 2 .COO).CH 2 [N(C 2 H 5 ) 2 ].HCl. Chiefly 
through its extensive use by Crile and by Bloodgood as a reliable 
local anesthetic to be depended upon in major surgical work, this 
drug has come into prominence in the last two or three years. 
It is said to be less toxic than other cocaine substitutes, and is a 
" prompt and powerful anesthetic." Novocaine is not strongly irri- 
tant. In practice it is often combined with some vasoconstricting 
drug like epinephrine. 

Other substances produce a degree of sensory anesthesia, as for 
example the coal tar phenol, creosol, etc. ; aconite, veratrine, etc. ; and 
the alkaloid yohimbine. 

V. 

Condensed Summary of Action. 

Cocaine is an alkaloid which has an initial general stimulating 
effect followed by narcosis and final paralysis as toxicity proceeds. 
Its peculiar interest is associated with its ability to produce local 
and temporary anesthesia which comes on about five minutes after 
application, and disappears in fifteen to thirty minutes with recovery 
of function. In local application it is peculiarly selective of sensory 
mechanisms but acts on all tissues. In spinal analgesia there is a 
local narcosis of the spinal cord and nerves originating therefrom, 
leading to loss of pain in that portion of the body the innervation 
of which passes through the local segment of the cord. In therapeutic 
quantity the central nervous system is at first stimulated, the effect 
passing over into depression and narcosis to a degree depending upon 
the concentration of the cocaine. The nerve structures readily re- 
cover from cocaine provided vital functions are maintained until the 
alkaloid is sufficiently oxidized or eliminated. Hence its toxicity is 
in large degree due to a true narcosis. The vital centers of the 
medulla are sharply stimulated by the therapeutic dose; respiration 
being accelerated, the tone of the vagus center increased, and the 
vasomotor center stimulated. The spinal cord is less vigorously 
influenced, but reflexes are at first accelerated, then depressed, the 
action being more acute on the sensory connections in the cord. The 
circulatory system is strongly stimulated. There is peripheral vaso- 
constriction chiefly from stimulation of the vasomotor center, but 



CONDENSED SUMMARY OF ACTION 221 

partially by local nerve-end stimulation. In local anesthesia the 
blood-vessels are characteristically contracted, leading to a blanching 
of mucous membranes, etc. The heart is influenced in opposite direc- 
tions by the simultaneous stimulation of the inhibitory nervous mech- 
anism and of the cardiac muscle. The nerve influence is more acute 
and briefer, hence is dominant in the earlier stage, while the muscular 
influence is dominant in the later stage. The amount of muscular 
work is increased, primarily through the action of cocaine on the 
voluntary motor nerves, but secondarily through a direct favorable 
influence on the striated muscle. However, consecutive tests on sol- 
diers and athletes indicate that the drug is of little or no permanent 
value. 

Locally applied to the eye, cocaine produces dilation of the pupil 
and partial loss of accommodation. The light reflex persists, hence 
the iris reflex mechanism is not affected. The dilation is due to 
stimulation of the nerve endings of the radial muscles. Cocaine 
is fully oxidized in the body, but sometimes a little is excreted through 
the kidney. There is a tendency to habit formation with a great 
increase in tolerance in the body. 



CHAPTER XXVIII. 
QUININE. 

I. 

Historical and Chemical. 

The bark of different species of the Cinchona tree, Cinchona 
succirubra, etc., yields a series of over twenty alkaloids of varying 
composition. Of these the quinine, quinidine, cinchonine, and cin- 
chonadine are of special importance. These alkaloids are quinoline 
derivatives as illustrated by the following formulae: 



HC 

I 
HC 



CH CH CH CH 2 C 9 H„NO CH CH 2 C y H 14 NO 



CH CH 3 G 

I I 

CH HC 



CH HC CH 

I I I 

CH HC CH 

n/v \/\y \x\/ 

CH N CH N CH N 

Quinoline Quinine Cinchonine 

II. 

Outline of Pharmacological Action. 

Quinine produces its results in the body because of its toxicity 
to protoplasm of all kinds, the action being strongest on undiffer- 
entiated protoplasm. It produces a very mild initial stimulative 
increase in function, followed by marked depression and loss of 
function, hence: 

1. Toxicity to protoplasm of all kinds. 

2. Specific, i.e., selective toxicity to undifferentiated protoplasm 
such as white blood corpuscles, malarial Plasmodia, etc. 

3. Antipyretic action by the primary decrease of heat production 
with secondary increase of heat loss. 

III. 

Details of Pharmacological Action. 

i. Systemic action. — The pharmacological effects of quinine are 
directly traceable to its great toxicity for all kinds of protoplasm. In 

222 



ACTION ON UNDIFFERENTIATED PROTOPLASM 223 

this regard it differs, however, from members of the aconite group 
in that the irritant and antecedent effects are very much lower and 
its depressing effects before the final intoxication occurs more pro- 
found. The general symptoms in the mammalian body are those de- 
pendent upon the general toxic activity throughout the organism. 
They will be better understood upon examining the behavior of dif- 
ferent tissues after subjection to quinine. 

2. Action on undifferentiated protoplasm. — The greater in- 
tensity of action of quinine on undifferentiated protoplasm accounts 
for its most important use, i.e., to destroy the malarial parasites when 
they infect the body. This therapeutic quality was discovered em- 
pirically early in the seventeenth century, long before the scientific 
reason was understood, either as regards the active alkaloid or the 
identity of the invading parasite. 

Binz x in 1867 determined that quinine was poisonous to certain 
one-celled animal forms, also to the white blood corpuscles. Vorti- 
eellae became inactive in 0.2 per cent, solution and actinophrys in 0.1 
per cent, withdrew its pseudopodia, its protoplasm became more gran- 
ular and darker. He showed that fresh water amebae are very sensitive 
to quinine, though, strange to say, the salt water forms are much 
more resistant. White blood cells kept at a temperature of 35° C. 
in a moist chamber are actively motile. "When mounted in serum 
containing 0.05 per cent, quinine this motility fails to develop and 
the white corpuscles remain round and darkly granular. 

Parasitic ameboid forms, such as the dysentery ameba and the 
malarial parasites, are also particularly susceptible to the influence 
of quinine. Quite recently its use has been advocated in rabies 
on the view that the Negri bodies are ameboid in nature. The 
malarial parasite runs a cycle of change in the body. It develops in 
the red blood corpuscles to a certain stage, then passes out into the 
blood plasma in an active free swimming form. This critical period 
in the life cycle of the malarial parasite is the one at which toxic 
substances are liberated into the body, and at this time the character- 
istic malarial symptom of paroxysms followed by fever occur. The 
motile malarial organism is peculiarly susceptible to quinine, hence, 
if it is present in the blood plasma in sufficient strength at this time 
the germs will be destroyed and their regeneration in a new cycle 
prevented. 

An influence in the body depending upon this general toxicity is 
felt on the white blood corpuscles, as can be demonstrated on the frog 

1 Binz, C: Archiv f. Mikroskopische Anatomie, Vol. III., p. 383, 1897. 






224 QUININE 

or the mammalian leucocytes. A prolonged and profound applica- 
tion of quinine may lead, therefore, to a reduction of the number 
of leucocytes, a fact which secondarily influences other conditions 
in the mammalian body. 

3. Quinine as an antipyretic. — The normal and constant tem- 
perature of warm-blooded animals depends upon regulating the heat 
through the interaction of two complex sets of factors: (1) the fac- 
tors that contribute to the regulation of heat production, and (2) 
the factors interacting for the regulation of heat loss or heat dissipa- 
tion. 

The production of the heat of the body is a direct result of the 
oxidations taking place during the metabolism of the tissues. Any 
and all factors which vary the intensity and amount of tissue oxida- 
tive changes will, of necessity, cause a variation in the amount of, 
heat produced. The most active tissues of the body are the muscles 
and glands, both of which are under nervous regulation and coordi- 
nation. But of all the heat producing tissues the greatest in mass 
and the greatest in intensity of oxidative process are the voluntary 
muscles. These are, therefore, the chief source of the body heat. 
Heat production takes place through oxidative changes in the skeletal 
muscles more or less independent of the liberation of active motion 
during the phenomenon of contraction (Pfluger's chemical tonus). 
The glands also produce considerable quantities of heat in pro- 
portion to their mass metabolism. Both these sets of organs 
vary in their oxidative activity under the influence of an elaborate 
nervous mechanism over which certain centers in the brain-stem have 
primary regulative influence. The chief center or centers that con- 
cern us in this relation are the thermogenic centers of the corpus 
striatum, the heat centers. Subsidiary centers are present in the 
mid-brain and the medulla, but the spinal animal does not possess 
regulative control of heat production. Heat production, therefore, 
may be varied by varying the activity of the thermogenic center. 
This center, like other nervous regulative mechanisms, is acting in 
response to the inflow of sensory stimulation and gives rise to nerve 
impulses in proportion to the sum of the algebraic factors, (1) 
volume of inflowing stimulation, and (2) the relative irritability of 
the center itself. As a matter of fact there are three instead of 
two links in the regulative chain controlling heat production. Be- 
side the two just given there is, (3) the condition which varies the 
ability of the terminal motor tissues to respond to a given nerve 
stimulus. There is a rise or fall of motor tissue stability under the 



ACTION AS AN ANTIPYRETIC 225 

influence of normal variations in the nutritive condition, or of patho- 
logical factors in the environment, both very prone to react through 
this third factor. 

Heat loss or heat dissipation is measured by the output of heat 
from the surface of the body through the three physical processes, 
a, heat radiation; b, heat convection, and c, heat loss through evapo- 
ration of moisture. Heat radiation and heat convection occur in 
proportion to the relative temperature of the surface of the body 
and its immediate environment. Loss of heat through evaporation 
of moisture bears a similar relation to environment, but is primarily 
dependent upon the amount of moisture thrown on the surface by 
the sweat glands. The surface temperature of the skin during the 
times when heat is being rapidly lost from that region bears a close 
relation to the volume of blood flowing through the skin per unit 
of time. Whenever the cutaneous blood-vessels are markedly dilated 
and there is an increase in the circulation of blood through the skin, 
there is a rise in surface temperature and heat loss through conduc- 
tion and radiation is greatly increased, unless perchance the external 
temperature is actually greater than that of the skin. Incidentally, 
the better cutaneous circulation is also favorable to increased activity 
of the sweat glands. 

Heat loss, therefore, is also regulated, i.e., coordinated by nervous 
mechanisms, in this case primarily two mechanisms, (1) the sweat 
secretory apparatus, and (2) the nervous factors which control the 
circulation, both general and local. When the sweat glands are stimu- 
lated by the secretory nerves there is a corresponding increase in the 
formation of sweat with its accompanying increased evaporation 
from the surface and resultant greater loss of heat. This stimulation 
of the sweat-producing apparatus is almost invariably associated 
with a corresponding stimulation of the vasodilator mechanism form 
the skin. 

It will be seen, therefore, that the constant temperature of the 
body involves the coordination of several nervous mechanisms, one 
group, the regulators of heat production, the other, the regulators 
of heat dissipation. These factors are maintained in balance at 
various levels in the different species of animals. 

Normal Temperature. 

Man 37°C. 

Dog 38°C. 

Rabbit 38.6°C. 

Guinea-pig 37.6°C. 

Chicken 41°C. 



226 



QUININE 



These heat levels in the given species are remarkably constant 
under the widely varying conditions of external temperature. Yet 
a slight disturbance of the relative irritability of any one of the 
various coordinative nerve centers may decidedly change the average 
temperature level at any time. This is illustrated by the results 
of puncture of the corpus striatum, also by fever resulting from 
the toxins of bacterial infection, or by other pathological conditions. 
Following brain puncture there is a gradual rise of level of heat 
equilibrium in an animal of from 1 to 3 degrees. Numerous studies 
of brain puncture, 1 have shown that there is an increase of heat 
production during the rise of temperature, rather than a decrease 
of heat loss. In other words, the puncture serves as a mechanical 
stimulus of the thermogenic center and this leads to a rise of heat 
production without a corresponding increase of heat dissipation suffi- 
cient to maintain the temperature of the body at the normal level. 
The result is that the temperature is raised. 



Two Experiments showing the effects of Heat Puncture in the Rabbit on heat pro- 
duction, heat loss and body temperature (from Schultze). 



Animal. 


Stage. 


Temperature 
Centigrade. 


Heat loss 


per hour. 


Heat produced per 
hour. 




Calories. 


Per cent, 
of normal. 


Calories. 


Pit cent, 
of normal. 


J 


Normal 

During rise 


38.5-38.6 
38.6-39.6 
39.6-39.5 


6.46 

6.87 
7.71 


100 
106 
120 


6.49 
7.67 
7.64 


100 

118 


| 


Climax 


118 










Normal 


38.7-38 9 
38.2-41.0 
41.0-41.2 
40.8-40.8 


7.22 
7.97 
8.70 
8.40 


100 
110 
120 
123 


7.28 
9.63 

8.88 
8.42 


100 


( 


During rise 


132 


n 


Climax 


122 


( 


Second day 


121 






At this new level, heat regulation can still be maintained. In 
other words, a shift in the point of heat equilibrium does not neces- 
sarily destroy the reflex responsiveness of either the thermogenic 
centers or of the blood vascular and sweat centers, the reactions of 
which control heat loss. 

In fevers, likewise, the disturbance of the balance between heat 
loss and heat production leads to a rise of temperature of the body 
but without loss of the temperature reflexes. In other words, there 
is a degree of heat regulation still shown under the fever condition, 
though the ability to maintain the temperature at the normal level 

1 Schultze, Otto: Archiv f. Path. u. Pharm., Vol. XLIIL, p. 193, 1900. 



ACTIOX AS AN ANTIPYRETIC 227 

is lost. Here, again, certain fevers depend upon a rise of heat 
production and the picture can readily be explained as a heightened 
irritability of the thermogenic center. 

Light is thrown upon the situation by considering what occurs 
under normal conditions during excessive physical activity. An 
enormous increase in heat production takes place with a rise of the 
temperature of the blood of the body. The increased temperature of 
the blood reacts through stimulation of the peripheral sensory mech- 
anisms, i.e., sense organs of heat, leading to reflexes that react through 
the centers concerned in both heat production and heat dissipation. 
The warmer blood flowing through these brain centers also acts 
directly on the nerve cells, especially those of the great medullary 
centers. The rise of blood-pressure within physiological limits also 
reacts on the nerve centers, contributing to an increase in their 
irritability. In the normal animal, under these conditions, the in- 
crease in irritability of the sweat and vascular centers is great 
enough to increase heat dissipation to a point that will quickly 
bring the temperature down to the normal, and in prolonged activity 
hold it there. In an animal in fever, in the case of puncture fever 
particularly, the stimulus falls directly on the thermogenic center. 
The mechanical stimulus of the puncture keeps this center in a state 
of hyperirritability which cannot be entirely overcome by the action 
of the heat dissipating centers. In fever from toxemia the phe- 
nomena are so similar that one may believe that there is a degree 
of toxic action (possibly selective) on the thermogenic center which 
increases its activity in a way comparable to the puncture fever. 

When quinine is given it leads to a fall of temperature, a change 
that is most pronounced if the body is already in the condition of 
fever. This fall of temperature takes place before there is a cor- 
responding increase in loss of heat, a complex that has been investi- 
gated by Gottlieb. This observation shows that the lowering of the 
temperature is in reality a primary lowering of heat production. 
Now quinine does not interfere with the output of carbon dioxide 
in normal animals, but it does result in a marked diminution in the 
excretable nitrogen. Tissue metabolism is therefore reduced, and 
since this reduction takes place when the brain and medulla are 
separated from the cord (Binz), it is evident that the primary in- 
fluence of quinine is directly on the tissues in which the heat is 
evolved rather than in the lowering of the irritability of the thermo- 
genic center itself or on the sensory side of this reflex arc. In fact 
the center is still reflexly responsive. However, in explanation of the 



228 QUININE 

favorable action of quinine in fevers dependent upon hyperirritability 
of the thermogenic center one can scarcely exclude a degree of 
narcotic action on this group of nerve t cells. 

Gottlieb 's experiments * show that the lowering of temperature 
will take place independent of change in heat dissipation. However, 
he observed that under certain conditions there was an actual lower- 
ing of the heat output. Quinine often produces a vasodilation in the 
blood-vessels of the skin and a corresponding increase in heat loss, a 
result that is readily explained by consideration of the toxic influence 
on the blood vascular system. If the toxicity leads to that degree of 
vascular paralysis in which the cutaneous vasomotor tone is lost, 
then this factor of heat dissipation assumes a more important role. 

The antipyretic action of quinine, therefore, is twofold: (1), 
chiefly a toxic lowering of tissue metabolism and therefore heat 
production, accompanied by a certain but slight degree of diminution 
of irritability of the thermogenic center; and (2), a secondary 
cutaneous dilation, especially in the rather toxic stage, with corre- 
sponding increase of heat loss. The absolute loss of course diminishes 
in the later stages of the reaction. The greatest antipyretic action 
of quinine is noted under pathological conditions or in brain punc- 
ture where the fever is due to hyperirritability of the tissues. But 
in normal animals there is also a lowering of temperature by quinine, 
showing that its peculiar influence is not limited to the special patho- 
logical case, but is general. 

4. Action of quinine on muscle. — Quinine is very toxic to skeletal 
muscle, producing a marked decrease in the power to do work. Even 
solutions of 1 in 50,000 are depressant to this tissue. The onset of the 
depressant action in the toxic concentrations is introduced by a brief 
and transient period of heightened irritability. The depressing ac- 
tion is proven to be directly on the muscle substance since it occurs 
when the nerve endings have been eliminated. 

Certain organs, such as the spleen, undergo a degree of contraction 
under the influence of quinine, which suggests that smooth muscle 
tissue has a somewhat greater initial stimulative reaction to quinine 
than most parts of the body. Larger doses produce depression of 
function. 

5. On the digestive tract and on digestion. — Quinine possesses 
a very bitter taste, hence reacts locally on the reflex mechanism of 
the mouth. The bitter taste leads to a strong reflex which givea 

1 Gottlieb, R: Schmiedeberg's Archiv, Vol. XXVI., p. 419, 1890. Also Vol. 
XVIII., p. 167, 1891. 



DETAILS OF PHARMACOLOGICAL ACTION 229 

quinine the indirect influence of a tonic. The character of the 
reaction of this class of drug is discussed more fully under the sub- 
ject of bitter tonics. Larger quantities of the more soluble hydro- 
chloride occasionally produce some local effects on the stomach leading 
to nausea, in some cases diarrhea. 

The digestive processes are lowered by a mixture of the enzymes 
with the quinine, presumably by direct destruction of the enzyme 
itself. 

6. On the liver. — Quinine leads to a depression of the glycogenic 
function of the liver. This reaction is explained as a result of the 
toxic lowering of the amount of glycogenic ferment due to the depres- 
sion of function of the liver parenchyma. 

7. On the central nervous system. — Beside the effect on the heat 
regulative center the general nerve structures undergo a depression 
of function ending in paralysis. This is demonstrated through the 
influence of the drug on the sensitiveness of the responses of the cere- 
bral cortex. There is often noted after relatively large quantities of 
quinine a distinct interference with the special sense organs, especially 
of the ear and eye, partial deafness being a peculiarly characteristic 
after result of the continued display of the drug. 

8. The elimination of quinine. — The alkaloid quinine is relatively 
insoluble and its absorption takes place only slowly from the alimen- 
tary tract. The hydrochloride is rather more readily absorbed be^ 
cause of its greater solubility. In the body a large quantity, 70 to 75 
per cent., is oxidized and disappears. The remainder is excreted 
unchanged by the kidney. Only traces of quinine are excreted in the 
feces. Schmitz 1 has carefully investigated this question. His results 
show that of the quinine administered by the mouth about one-fourth 
to one-third is slowly regained from the urine. The following figures, 
quoted from him, illustrate this point. 

Experiment I., 0.817 gr. quinine given, .217 gr. recovered = 26.6 per cent. 
II., 0.817 gr. " " .244 gr. " =29.9 

III., 1.226 gr. " " .346 gr. " =29.7 

When the quinine was introduced subcutaneously it was excreted more 
slowly, as shown in the following table, also from Schmitz: 

3 Schmitz. Richard: Schmiedeberg's Archiv, Vol. LVL, p. 301, 1907. 



230 



QUININE 



Day. 


Quinine given 
daily. 


24 hour urine 
in cc. 


Quinine 
recovered. 


Per cent. 


Second 


] r 

i i 

Y 0.605 ■{ 

l 
J I 


1400 
1700 
1400 
1450 
1600 
1500 


0.108 
0.120 
0.083 
0.128 
0.076 
0.071 


17.9 


Third 


19 8 


Fourth ' 


13.7 


Fifth 

Sixth 


21.1 
12.6 


Seventh 


11.7 







This shows an average daily recovery of 16.1 per cent, of the 
amount of quinine given. 

The human body does not acquire any marked tolerance, as shown 
by the usual method of determination by the increased power of oxida- 
tion. This Schmitz determined on an individual who excreted an 
average of 25.3 per cent, of the quinine given during the first seven 
days, while five weeks later he excreted 26.9 per cent. 

IV. 

Condensed Summary of Action. 

Quinine and its closely related alkaloids are protoplasmic poisons 
which show a minimum initial stimulation and a prolonged paralytic 
after effect. Undifferentiated tissues, such as the white blood cor- 
puscles, the general type of tissue cells, as connective tissue, etc., and 
micro-organisms, such as amebae and the malarial parasites, present 
the greatest susceptibility, approaching that of specific reaction. 

As might be expected, quinine is an antipyretic of value. There 
is a decrease in body temperature in the normal body, but a more 
conspicuous decrease occurs in fevers. The reduction is primarily 
through depression of the function of the thermogenic tissues. The 
muscular tissues show an initial slight stimulation chiefly in con- 
tractility, followed by a marked depression of ability to do muscular 
work. This effect is true for skeletal muscle, cardiac muscle, and 
smooth muscle. The nervous system is depressed by the lowering 
of the irritability of the nerve cells of whatever type. The effect 
shows itself through interference with the action of the cortex in 
interpreting visual and auditory sensations and with other coordina- 
tive centers of the central nervous axis. There is a slight bitter 
tonic effect on the digestive tract, but this is more than counter- 
balanced by the lowering of the efficiency of the digestive enzymes. 
Quinine is very readily absorbed from the alimentary tract, is slowly 
oxidized by the tissues and excreted unchanged to the extent of 25 
to 30 per cent, by the kidney. 



H. The Coal Tar Series 

CHAPTER XXIX. 

THE COAL TAK ANTIPYRETICS. 

I. 

Historical and Chemical. 

The chemical separation of the coal and wood tar products lias 
yielded a long series of carbon compounds, many of which have im- 
portant influences on the functions of the body. The most important 
of these compounds pharmacologically are those that have as their 
base the benzine nucleus, often, it is true, fundamentally modified. 

The distillation of many woods and wood tars also, especially of 
the pines, beeches, etc., yields compounds of this series, of which the 
creosotes are an illustration. 

The coal tar products are characterized by their toxic influence on 
living protoplasm, a toxicity that varies widely with the exact com- 
pound. But for convenience in presenting their pharmacological 
actions the numerous members of the series will be treated in two 
sub-groups : the Antipyretics and the Antiseptics. 

The older antipyretics are such drugs as aconite and quinine. 
These, in recent times, have been very largely superseded by the 
antipyretics of the coal tar series. The introduction of phenol as an 
antiseptic by Lister x in 1867, which so profoundly revolutionized 
our surgical technique, was soon followed by the important discovery 
that its carboxyl derivative, salicylic acid, produced a marked fall 
of body temperature. This antipyretic action of salicylic acid was 
soon extended to phenol itself and to others of the simpler phenol 
series. 

The almost limitless possibility of variation in structure of both 
nucleus and side chain among the ring compounds has led to the iso- 
lation, and, in many cases, synthetic production of numerous com- 
pounds, which are theoretically possible, according to the laws of 
chemical substitution. 

1 Lister, Sir Joseph: British Medical Journal, Sept. 21, 1867. 

231 






232 THE COAL TAR ANTIPYRETICS 

Phenol is sharply toxic to protoplasm and its antipyretic action 
is secured with danger. The attempt has been to reduce toxicity 
and if possible retain or strengthen the antipyretic action. Many of 
these preparations have been manufactured and thrown on the market, 
often under trade names, and without adequate therapeutic testing. 
Of the series that have proven of distinctive antipyretic value and 
which have now been used and tested through a number of years 
until their pharmacological actions are well proven may be mentioned : 

(1) Acetanilide, an analine derivative with the formula: 

CH 

HC CH 
C 6 H 6 NH.CO.CH 3 = || | 

HC CH 

\^ 
CNH.CO.CH 2 



(2) Antipyrene, which is a phenyl-dimethyl-isopyrazolon, with 
the formula : 

CH 3 C = CH 

I I 
C 6 H 6 N.N(CH 3 ).C(CH 3 ).CO.CH = CH 3 N CO 



N.C B H e 

(3) Acetphenetidine (phenacetine), with the formula: 

CNH.CO.CHs 
/^ 
HC CH 
C 6 H 4 OCHaCHs.NH.CHsCO = II | 

HC CH 

\^ 
CO.CH 2 .CH 3 

To this series one might add members of the group of salicylates, 
which have considerable antipyretic action. Especially to be men- 
tioned are ethyl salicylate (oil of wintergreen) and acetyl salicylic 
acid (aspirin). 



OUTLINE OF PHARMACOLOGICAL ACTION 233 

II. 

Outline of Pharmacological Action of the Coal Tar 
Antipyretics. 

The chief activity of the subgroup is expressed by the name, and is 
therefore : 

1. Antipyretic. 

2. A tendency to reduce oxy -hemoglobin to methemoglobin. 

3. General toxicity. 

4. Analgesic action. 

5. Initial slight stimulation, followed by prolonged depression 
and paralysis of differentiated tissues, intensity of action greatest 
for nervous tissue. 

III. 

Details of Pharmacological Action. 

i. The general antipyretic action. — Under the chapter on 
quinine a review of the normal mechanism for the regulation of heat 
in the body for those animals that have a constant temperature is 
given. Attention is called there to the two regulative factors, 
heat production and heat dissipation, both of which are under 
nervous control. It is there explained that heat production which 
takes place in the tissues is regulated through definite nervous cen- 
ters in the brain-stem. Heat loss, on the other hand, is a factor of 
heat dissipation from the surface of the body. So far as the body 
is concerned, the rate of loss of heat and its regulation will depend 
chiefly on variations in the two factors, i.e., the circulation through 
the skin and the activity of the sweat glands. 

The coal tar antipyretics depress the vasomotor tone, hence lead 
to marked vasodilation, particularly in the skin. This physiological 
change produces an immediate increase in the relative warmth of the 
skin, a factor which is favorable to the loss of heat. The change in 
the circulation in the skin favors an increase in sweat production, 
adding still a third factor favorable to heat loss. In the therapeutic 
intensity of action the thermogenic center is still responsive to 
stimuli, hence at this stage there will be an associated actual increase 
in heat production. Under the more pronounced influence of the coal 
tar antipyretics the activity of the thermogenic center itself is de- 
pressed, hence there is a decrease in heat production. These factors 



234 THE COAL TAR ANTIPYRETICS 

were determined on rabbits by Gottlieb. 1 He contrasted the anti- 
pyretic action of quinine and the coal tar products, showing that 
whereas quinine primarily depresses thermogenesis with little or no 
change in heat loss, antipyrine greatly increases the heat dissipation, 
which is the primary source of its ability to depress the body tempera- 
ture. In the more intense action it also decreases heat production, a 
factor that is relatively secondary in this group. 

2. Narcotic action of the antipyretics on the central nervous 
system. — The antipyretics as one characteristic of their action pro- 
duce a decrease in the sensitiveness of the nerve centers to reflex 
stimulation, therefore are analgesic. This narcotic factor has led to 
their use (and abuse) in cases of severe migraine. Acetanilide, which 
is the most widely used in this connection, is decidedly, in fact dan- 
gerously, toxic. Even with mild dosage there is some depression of 
reflex irritability, indicated by a greater drowsiness and sluggish- 
ness than normal. In toxic quantity acetanilide produces cyanosis 
and convulsions in both man and mammals. These latter effects have 
been ascribed to lack of coordination of the nerve reactions through 
the spinal cord to a degree approximating to strychnine poisoning. 
The convulsions are to some extent, but by no means wholly, traceable 
to the cyanosis and asphyxiation, which occur at the same time. 

3. On the circulation. — The effects of the coal tar antipyretics 
on the circulatory system are threefold : First, cardiac ; second, vaso- 
motor; third, on the blood. 

Studies on the frog's heart show that the initial rhythm is ac- 
celerated, but that this is followed by decided cardiac slowing. The 
cause of the behavior of the heart is best shown by studies on isolated 
heart muscle. The toxic action can readily be shown on isolated 
strips of terrapin heart. This line of experimentation shows that it 
takes careful gradation of dosage to develop the stimulating action 
of the antipyretics, for example, acetanilide. Solutions of from 0.02 
to 0.04 per cent, of acetanilide in weak Ringer's solution or in physio- 
logical saline lead to acceleration in the rhythm of heart strips, occa- 
sionally accompanied by increased amplitude. But a very slightly 
stronger solution, while it may produce one or two beats with ac- 
celerated rhythm, invariably leads to slowing and sometimes complete, 
cessation of the rhythm. 

Toxic solutions (up to saturation, i.e., 0.5 per cent.) produce a 
slow and weak rhythm followed by a pause. The initial contractions 
may be more or less incoordinated and show a tendency to fibrillation. 

1 Gottlieb, R.: Archiu f. Exper. Path. u. Pharm., Vol. XXVI., p. 419, 1890. 



ACTION ON THE CIRCULATION 235 

Even these solutions are not immediately toxic, since after strips 
are returned to normal solutions they finally recover fully. It is 
evident, therefore, that acetanilide produces its effect in the frog's 
heart too by a narcotic depression of cardiac muscle. 

The blood-vessels are dilated under the antipyretics, a condition 
which may be preceded by a slight but insignificant vascular constric- 
tion, with associated higher blood-pressure. Certainly in the toxic 
stage the blood-pressure is low, the blood stream stagnated with pro- 
nounced cyanosis. These effects are due to the general paralysis of 
the vasomotor nervous mechanism, leading to a reduction in the 
resistance to peripheral blood flow. However, the cardiac depression 
will also account for some percentage of the decrease in blood-pressure. 

The Mood is affected through the formation of methemoglobin, es- 
pecially marked with acetanilide, though with antipyrine the action 
does not take place to so profound a degree. As the dose is increased 
and the toxic action comes on the disintegrating red blood cells set 
methemoglobin free in the blood stream. It is finally excreted by the 
kidney and makes its appearance in the urine. The methemoglobin 
action is produced largely by the decomposition product, para-amido- 
phenol, which occurs on oxidation of acetanilide in the body. The 
fact that antipyrine is not so readily oxidized and does not so rapidly 
give rise to this compound explains its failure to produce oxy-hemo- 
globin. Of the three representatives of the series chosen, acetanilide 
is the most toxic to the blood and phenacetine the least. 

4. Variations in susceptibility. — There is unusual variation in 
individual susceptibility to the members of the coal tar antipyretic 
series. The general literature notes numerous cases of recovery after 
enormous doses, and at the same time of deaths that have occurred 
from relatively small doses. Children are particularly susceptible, 
and a greater reduction in dosage allowance for them than is called 
for by the rule must be made. In children the tissues are in an 
active stage of growth. Their protoplasm is relatively undifferen- 
tiated, and, as is true for most substances toxic for general proto- 
plasm, their tissues are particularly susceptible to chemicals of this 
series. 

The narcotic action of the coal tar antipyretics has led to their 
extensive use in the so-called headache remedies, a use fostered to an 
undesirable degree by chemical manufacturers and of course by the 
medical charlatans. The methods contributing to the extensive use 
of these drugs as home remedies are responsible for a large percentage 
of the fatalities that have occurred therefrom. The toxicity of the 



236 THE COAL TAR ANTIPYRETICS 

series is entirely too great to justify use except under the direction of 
a physician. The abuse of this principle has resulted in numerous 
cases of collapse and an occasional death that might otherwise have 
been prevented. 

5. Comparison of acetanilide, antipyrine, and acetphenetidine. 
— Of the three drugs the least toxic, possibly because it is least soluble, 



Acetanilide 
NaHCO s . 

Acetanilide. 

Acetanilide 
Caffeine 
jVaffC0 3 . 

Acetanilide 
Caffeine. 



Fig. 62. — The relative toxicity of acetanilide in combination with sodium bicar- 
bonate and caffeine. From Worth Hale. 

is acetphenetidine ; the most toxic, antipyrine. Acetanilide particu- 
larly is oxidized in the body to para-amido-phenol, to which form 
its general effects are often ascribed. The phenol acts on the red 
blood corpuscles, producing methemoglobin. The antipyrine also pro- 
duces methemoglobin. It is oxidized to the para-amido-phenol more 
slowly, hence the substance can be taken care of by the body without 
so intense a reaction with the hemoglobin. Worth Hale has demon- 
strated that caffeine added to acetanilide greatly increases its toxicity. 
Sodium bicarbonate tends to reduce the toxicity of acetanilide, also 
the toxic action of acetanilide and caffeine. 



CHAPTER XXX. 
THE COAL TAR ANTISEPTICS. 

I. 

Historical and Chemical. 

The coal tars yield a long series of antiseptics, i.e., drugs which 
are particularly toxic to generalized protoplasm, and therefore to 
bacteria and other lower organisms. 

An ideal antiseptic for the human body is one that is toxic to any 
foreign invading organism, bacterial or otherwise, and at the same 
time non-toxic for the tissues of the body itself. It is expecting too 
much to suppose that we can with our present state of chemical 
knowledge attain this ideal, but the goal is worth striving for, and 
the works of such men as Ehrlich give promise that we may reach it 
at a day not so very far distant in the future. That the protoplasm 
of bacterial organisms is similar to that of the human organism in its 
fundamental composition cannot be denied. That there is a differ- 
entiated structure for bacterial protoplasm also goes without saying. 
The point to be desired in the antiseptic is that it may so chemically 
combine with some characteristic structure of the organism as to 
become toxic without at the same time forming disadvantageous 
combinations with the protoplasm of the tissues of the host. The suc- 
cess of Ehrlich in synthetically developing the organic arsenic com- 
pound, arsenobenzol, stands to-day as our best illustration of the 
modern tendency of research in this field. 

Benzene, C 6 H 6 , the base or nucleus on which are built nu- 
merous series of coal tar preparations, is practically incapable of 
chemically combining with protoplasm. But this nucleus is chemically 
wonderfully labile, since it permits of innumerable substitutions for 
the hydrogen atoms of the ring, and, as we have already seen in the 
antipyretics, for the carbon as well. The substitution products carry 
the ability to attach the ring to the chemical substances entering 
into the composition of protoplasm. As an example, when one hydro- 
gen is substituted by one oxy-hydrogen, phenol is formed. 

237 



238 THE COAL TAR ANTISEPTICS 

OH 

Phenol - ! 



Phenol is wonderfully toxic to protoplasm, therefore antiseptic. 
The toxic and antiseptic properties of the benzene nucleus increases 
with the number of attached OH groups in the order illustrated by 
the following: 

Toxicity increases from Phenol to Pyrogallol 
OH OH OH 



OH 



OH 
OH 



V \s \/ 

Phenol Resorcin Pyrogallol 

The toxicity is due to two factors, (1) the greater combining 
ability, and (2) the property of the hydroxyl grouping. 

The toxic and antiseptic action of the phenol compounds is 
changed somewhat with the introduction of other nuclei in the side 
chain, as, for example, in salicylic acid or in methyl salicylate. 



OH OH 

I I COOH I I COO.CH< 



V 

Salicylic acid Oil of wintergreen 

Salicylic acid is much less toxic to the human body than phenol. 
This property makes it less irritant to mucous surfaces. Its some- 
what lesser degree of solubility in the tissue fluids also reduces its 
toxicity. The introduction of other radicles, such as methyl, CH 8 , 
etc., adds the pharmacological action of the new group, which may 
cause variation either in the stimulative phase or in the toxic phase 
of the action of the original product. 

The antiseptics of the coal tar series also owe their toxicity in 
some degree to the decomposition products, as is illustrated very well 
by the explanation of the methemoglobin formation in the case of 
acetanilide. In the body these decompositions may set free active 
antiseptic compounds, as illustrated by salol. 

Salol Decomposition products 

OH OH OH 

I I COO II || 



Phenol Salicylic acid 



PHARMACOLOGICAL ACTION OF COAL TAR ANTISEPTICS 239 

In like manner the body protects itself by the formation of inert 
compounds. The phenols and phenol derivatives are largely oxidized 
to phenol sulphate and other relatively inactive compounds, in 
which form they are rapidly excreted by the kidney. 

OH 

I I O.S0 2 .OH 

\/ \/ 

Phenol Phenol sulphuric acid 

It would be out of place to treat specifically every member of this 
enormous group of compounds. For our purpose it will be better to 
illustrate the group by specific treatment of the most important 
types. For this purpose we will take (1) the phenols, (2) the sal- 
icylates, and (3) the creosotes. 

II. 

Outline of Pharmacological Action of the Coal Tar 
Antiseptics. 

1. General toxicity for all kinds of living protoplasm. 

2. This toxicity manifests itself in an initial but slight stimulation 
pliase, followed by a narcosis and paralysis. 

3. Peculiarly toxic to the nerve centers of the central nervous 
system. 

4. A certain degree of anesthesia to local sensory mechanisms. 

5. Toxic to the blood with the formation of methemoglobin. 

I. 

THE PHENOLS. 

Phenol, or carbolic acid, is the oldest and best known of the coal 
tar antiseptics. It is derived from benzol by the substitution of one 
hydroxyl, thus, C 6 H 5 OH. It was phenol which Lister first introduced 
into antiseptic surgery in 1867. 1 

III. 

Details of Pharmacological Action. 

i. Toxicity to protoplasm. — Phenol owes its antiseptic quality 
to its solubility in, and toxic chemical avidity for, protoplasm. It 

1 Lister, Sir Joseph: "On the Antiseptic Principle of the Practice of 
Surgery," British Medical Journal, Sept. 21, 18C7. 



240 THE COAL TAR ANTISEPTICS 

acts somewhat more strongly on undifferentiated protoplasm, such 
as bacteria, protozoa, etc., but it is relatively toxic for all kinds of 
differentiated tissue. As an antiseptic to be used in surgical sterili- 
zation and dressings, it is customary to use solutions of from 3 to 5 
per cent. The latter solution is not only germicidal, but quite toxic 
for exposed tissues, hence when kept in long contact leads to de- 
generation and disintegration. 

More dilute solutions of phenol will destroy active bacteria if 
kept in contact for a sufficient length of time, in the course of a few 
minutes with certain forms, while others resist for hours or even 
days. Bacterial spores are the most resistant forms of living matter 
to the action of chemical poisons. The spores of anthrax are particu- 
larly resistant in this regard. They withstand the toxic action of 
the stronger solutions of phenol for many hours. 

The typical action of phenol on general protoplasm is the pro- 
duction of a degree of local irritation. This is especially the type 
of action when phenol is applied to mucous membranes. "When car- 
bolic acid is swallowed the local corrosive action on the mouth and 
stomach leads to irritation accompanied by the reflexes expressed in 
nausea and vomiting. This is particularly true of gastric irritation 
from this source. Such reflexes may and often do follow non-toxic 
amounts of the drug. Phenol is easily soluble and readily absorbed, 
therefore, in addition to the local reflexes from gastric irritation, the 
substance quickly produces its systemic effects, especially when there 
is a possibility of being absorbed through abraded surfaces. 

2. On the central nervous system. — Carbolic acid produces a 
slight and transient stimulation of the cells of the central nervous 
system, but the main picture is one of toxic depression and collapse. 
The collapse appears early and after a relatively slight amount of 
absorption. It is due to the action of phenol on the basic nuclei of 
the brain-stem and cord. The initial stimulating effect on the great 
regulative centers is slight, but shows itself through rapid respira- 
tion, accelerated pulse, and other vascular disturbances. The stage 
of toxic collapse quickly follows through a depression of, (1) the ir- 
ritability of the thermogenic center, which leads to a lowering of 
heat production, (2) through a paralysis of the vasomotor and cardiac 
centers of the medulla, deranging the efficiency of the circulation, and 
(3) by paralysis of the respiratory center leading to shallow respira- 
tion, asphyxia, and death. The spinal cord is affected in such a way 
as to interfere with the coordinative control of voluntary nerve im- 
pulses. It is apparently this which leads to the irregular contrac- 



ACTION ON THE CIRCULATORY SYSTEM 241 

tions and muscular twitchings, both in the frog and in the mammal, 
resulting in response to sensory stimulation. The absorption of 
phenol is so rapid after the swallowing of toxic quantities that this 
chain of nervous symptoms follows in rapid succession, a fact only 
too well known from the numerous cases of suicidal poisoning. 

3. On the circulatory system. — The toxic action on the medullary 
centers mentioned above of course includes those centers controlling 
the circulatory apparatus. In therapeutic limits the first influence on 
the circulatory centers is slightly stimulative. This limit is quickly 
passed, and there is a marked depression, which shows itself most 
strikingly on the vasomotor center. "With the decrease of response 
of this center there is dilation of the peripheral blood-vessels and 
fall of blood-pressure, all contributing to the well-known condition of 
collapse. The cardiac muscular tissue is also affected by phenol. 
Perfusions of the heart, as, for example, in the frog, with very dilute 
phenol solutions (.005 per cent.) lead to an increase in both ampli- 
tude and rate. With stronger solutions of phenol this favorable 
picture is changed to one of marked depression, showing an evident 
direct muscular toxicity. The circulatory system, therefore, contrib- 
utes sharply to the total picture of collapse under the influence of 
phenol. 

4. The excretion of carbolic acid. — Small amounts of phenol are 
adequately taken care of by the body of man and eliminated in 
more or less oxidized form, the oxidation taking place through the 
hydroxyl bond. Phenol is oxidized into phenol-sulphuric and glycu- 
ronic acids, which leave the body by way of the urinary system. 

In the oxidation and excretion of phenol, the toxic drug is brought 
into intimate contact with the renal cells and may produce there 
local intensity of action sufficient to produce nephritis. As a result 
the cells of the renal tubules, both of the capsule and the secreting 
tubules, may undergo toxic degeneration and necrosis, if excretion is 
rapid enough to produce a sufficient concentration of the drug about 
the tissues. This is one of the great dangers from the use of benzol 
compounds as physiological antiseptics. On the other hand, a certain 
mild degree of local antisepsis may be produced in the excreting 
organs because of the interaction of the factors just mentioned. 

5. Toxicology. — The toxicology of phenol is assuming wide prac- 
tical importance because of its ever increasing use with suicidal 
purpose. The extensive use of the antiseptic in the arts and for 
practical disinfection makes it a substance easy for the layman to 
obtain. Its terrific corrosive action is enough to deter any one from 






242 THE COAL TAR ANTISEPTICS 

so unfortunate a choice of suicidal drugs as phenol, but this factor 
is, probably because of ignorance of the fact, given little weight by 
our numerous despondents. One gram or less may be a fatal dose, 
though two or three times this amount may be safely eliminated by 
the body if introduced through sufficient time. For example, in the 
days of the use of the Lister carbolic acid spray in surgical work it 
often happened that large enough quantities were inhaled by the 
surgeon to produce distinct depression, though no acute toxic effects. 
Both the absorption and excretion of phenol are rapid, hence the 
toxic dose will depend largely upon the concentration as well as on 
the rapidity of introduction. A quantity toxic when suddenly intro- 
duced into the stomach may not be so if taken in a series of smaller 
doses. The stage of collapse and death may come on in 20 to 30 
minutes, while death may be delayed for 12 to 24 hours. 

In case of poisoning the remedies should be directed toward quick 
and decisive removal of the non-absorbed phenol, and be followed by 
symptomatic treatment. Externally phenol is best removed by wash- 
ing with alcohol or the stronger alcoholic liquors, which dissolve and 
thus eliminate the drug. When these solvents are not available, then 
olive oil, sweet oil, or vaseline may be used, as the oils are phenol 
solvents. Internally phenol may in some cases be dissolved in weak 
liquors and at once removed by the stomach pump, or it may be par- 
tially neutralized by the use of lime water, permanganates, or 
sulphates. The sulphates do not react with phenol externally, 
but are an aid to the body in the formation of phenol sulphates 
during systemic poisoning. Sollmann has shown that too much 
reliance should not be placed on the sulphates in the case of 
acute poisoning, although the sulphates are somewhat counteract- 
ing in their systemic effects, because they also stimulate where 
phenol depresses. 

Salol is itself not strongly active, but after it passes out of the 
stomach and is brought into contact with the alkaline contents of 
the intestine it is broken down into phenol and a salicylic acid com- 
ponent. The released phenol now becomes actively antiseptic, while 
the salicylic acid produces its typical antipyretic and antiseptic 
action. 

Resorcin, di-hydroxy-phenol, and pyrogallol, tri-hydroxy-phenol, 
are very much more toxic than phenol, the toxicity increasing with the 
number of OH ions attached. These compounds are still more highly 
irritant to the tissues. The latter especially is peculiarly toxic to 
the blood, breaking down the red blood corpuscles with the formation 



CONDENSED SUMMARY OF THE ACTION OF PHENOL 243 

of methemoglobin. These chemicals are now primarily of interest 
because of their toxicology. 

IV. 

Condensed Summary of the Action of Phenol. 

Phenol, or carbolic acid, is an irritant toxic mono-hydroxy-benzol, 
which is toxic to all living protoplasm. The di-hydroxy resorcinol 
and tri-hydroxy-pyrogallol produce the same type of changes, though 
they are more intense in action and more toxic. When applied locally 
phenol produces a degree of irritation, and, if concentrated, corrosion 
and death of the tissue, whether this be epidermal or mucous mem- 
brane. It is rapidly absorbed into the general circulation. The 
systemic effects are slight and transient stimulation, followed by 
rapidly developed depression and paralysis. This effect shows most 
strongly on the central nervous, system, particularly the basic nuclei, 
in which the paralysis leads to depression of the heat regulative 
center, as well as of the vasomotor and respiratory centers. The 
general toxic action on the nervous system quickly leads to uncon- 
sciousness and systemic collapse, from which the individual does not 
recover. The motor tissues, the glands, skeletal muscle, smooth 
muscle, and heart are all sharply depressed, showing a lowering of 
general metabolism and of specific functional activity. The heart 
itself is at first accelerated, then weakened and paralyzed by direct 
action on the cardiac muscle. 

Phenol is rapidly excreted from the body, chiefly after oxidation 
to sulphates, in which form the substance is less toxic. In the process 
of elimination through the kidney a degree of local irritation is 
produced, leading to nephritis with necrosis, conditions that develop 
particularly in prolonged or chronic poisoning. 

On account of the toxic action of phenol it is of peculiar value as 
an antiseptic and disinfectant. For surgical antisepsis from 3 to 5 
per cent, solutions are used, though the stronger solutions must be 
guarded from too prolonged contact and too excessive absorption. 
Most bacteria readily succumb to these strengths of carbolic acid, but 
some species, especially anthrax, in particular the spores, are pecul- 
iarly resistant. For local cutaneous antisepsis it is now the practice 
to use concentrated phenol for a few moments of contact, then wash 
off the phenol with 95 per cent, alcohol. 

As a disinfectant for sputum, excreta, etc., 10 per cent, phenol 
is used, leaving the material to be disinfected in contact for several 



244 THE COAL TAR ANTISEPTICS 

hours. This will kill all but the most resistant spore-forming bacteria, 
and these can be killed by prolonging the contact with phenol. 



II. 

SALICYLIC ACID AND THE SALICYLATES. 

I. 

Details of Pharmacological Action. 

i. Toxicity to general protoplasm. — The salicylic acid group is 
relatively very much less toxic than phenol. The substitution of a 
carboxyl radicle leads to a great decrease, but far from a loss in 
irritant properties of the compound. Therefore these compounds 
are much more mildly toxic to animal tissues than the phenol, from 
which they are derived, but are none the less valuable as antiseptics. 
Solutions of 0.1 to 0.2 per cent, are ordinarily sufficient to prevent 
the growth of bacteria. The more undifferentiated types of proto- 
plasm are also more strongly influenced by salicylic acid and the 
salicylates. 

Salicylates in the body, presumably due to their initial stimulat- 
ing effects, lead to an increase in the number of leucocytes, a factor 
that is by some thought to be the explanation of the favorable activity 
of these compounds in the clinical treatment of rheumatism. 

2. On the central nervous system. — Salicylic acid in contrast 
with phenol is more stimulating and less depressant to the centers 
of the brain and cord, hence its action is more in line with that of the 
antipyretics than is phenol. In fact the salicylates formerly enjoyed 
a popularity as antipyretics, a position dependent upon the depres- 
sion of the thermogenic center and their toxic influence on tissue 
metabolism in general. 

Hanzlik, 1 who has studied the toxicity of the salicylates, states 
that when salicylate is given in doses of from 10 to 20 grains per 
hour signs of toxicity appear after from 180 to 200 grains. ' ' Toxicity 
is indicated by the appearance of headache, nausea, vomiting, ringing 
in the ears or deafness, rarely delirium and hallucinations, and some- 
times diarrhea.' ' The toxicity is somewhat greater with other salicy- 
lates, as indicated by the table below. 

1 Hanzlik, Paul J.: Jour. American Medical Ass'n, Vol. LX., p. 957. 1913. 



ACTION ON THE ALIMENTARY CANAL 245 

TABLE I 

The Mean Toxic Doses of the Various Salicylates (Hanzlik). 



Drug. 



Synthetic sodium salicylate 

Natural sodium salicylate 

Methyl salicylate (oil of gaultheria). 

Acetylsalicylic acid (aspirin) 

Salicylosalicylic acid (diplosal) 



Mean Toxic Dose 
(gr.) 



180 
200 
120 minims 
165 
100 



The average dose given in the table is for adult men. For women 
the toxic quantity is 80 per cent, of the above, i.e., proportional to 
the difference in weight. 

3. On the circulatory system. — The salicylates depress the circu- 
latory system. This occurs from the fact of toxic depression of the 
vasomotor center on the one hand, and the direct deleterious influence 
on the muscles of the blood-vessels and of the heart on the other. 
Acetyl salicylic acid, for example, produces practically no favorable 
change in the contractions of the frog heart, but when the drug is 
sufficiently concentrated (0.001 per cent.) slows the rhythm and ulti- 
mately to the point of complete suppression. In perfusion experi- 
ments the cold-blooded heart may be revived, but only after a long 
latent period, much longer than required for most drugs of this type 
tested by physiological assay. It is inferred that this toxic action is 
a factor in the toxic picture in therapeutic practice. 

4. On the alimentary canal. — Salicylic acid and the salicylates 
are readily absorbed from the alimentary tract. They are slightly 
irritant to the mucous surfaces and interfere to a degree with the 
normal digestive processes, owing to the fact that they lower the 
efficiency of the chemical processes in digestion, 1 per cent, solution 
decidedly diminishing the enzyme action of the digestive ferments. 
The nausea and vomiting after salicylates are largely of central 
origin. Waddell 1 says that vomiting is an early symptom in cats, 
occurring in from 20 to 90 minutes after salicylates by the mouth. 
He found that " Emesis follows on hypodermic injections of salicylates 
after a latent period of at least 20 minutes." Salicylates were not 
found in the vomitus, a fact greatly strengthening the conclusion 
B8 to central origin of the disturbance. The emetic dose for cats is 
given as 0.6 grm. per kilo of body weight, the toxic dose, 0.9 to 1.1 
grms. per kilo in cats. 

1 Waddell, J. A.: Archives of Internal Medicine, December, 1911. 



246 THE COAL TAR ANTISEPTICS 

5. The antipyretic action. — The simple salicylates are distinctly 
antipyretic, though not so valuable as the acetanilide series. Their 
action is multiple. The thermogenic center is markedly depressed, 
thus lowering the general heat production in the body. At the same 
time there is a stimulation of the sweat producing glands in the skin 
associated with cutaneous vascular dilation, thus decidedly increas- 
ing heat dissipation. 

6. Acetyl-salicylic acid.— C 6 H 4 (CH 3 CO).COOH. (aspirin). 
This compound " acts like salicylic acid, over which it possesses the 
advantage of producing less of the undesired local and systemic side 
effects, on account of the slow liberation of the salicylic acid. It is 
said to pass the stomach unchanged, the decomposition beginning in 
the intestine. ' ' * 

Acetyl-salicylic acid has distinct toxic properties indicated by its 
influence on the nervous system. The therapeutic dose occasionally 
produces distinct dizziness, weakness, and sometimes fainting. 
Idiosyncrasy is sometimes present, and clinical cases are reported 
where a single five-grain dose has led to marked cyanosis and edema. 
The drug produces a depression of the efficiency of the circulatory 
system with a great weakening of the activity of the heart. The 
perfused frog heart retains its usual sensitiveness to vagus regula- 
tion, even when the cardiac muscle is on the point of yielding its 
rhythm, which it does to a concentration of 0.001 per , cent, in the 
usual artificial perfusion solutions. 

This compound also has the usual amount of antiseptic power 
and is said to be more readily borne by the body than other forms 
of the salicylate series. 

II. 

Condensed Summary of the Action of the Salicylates. 

Salicylic acid and the salicylates are less corrosive than phenol 
and its hydroxy series. Salicylic acid is also readily absorbed into 
the general circulation, and produces a slight degree of local irrita- 
tion, but no corrosion of the absorbing surface. The systemic effects 
are those of a mild stimulation, followed by prolonged depression and 
mild narcosis. On the central nervous system this leads to a de- 
crease in the reflex sensibility, particularly of the higher centers 
of the cortex. There is depression of the thermogenic center as well 
1 New and Non-official Remedies, p. 225, 1914. 



SUMMARY OF ACTION OF SALICYLATES 247 

as of the peripheral heat producing mechanisms, hence the salicylates 
are of importance as antipyretics. The initial therapeutic action on 
the circulation is to slightly increase blood-pressure. This is partly 
due to an increase in vasomotor tone through the regulating nerve 
centers. The later effects are just the opposite because of the narcosis 
of this nerve center. There is a toxic depression by direct muscular 
action on the heart. Respiration is at first slightly increased, followed 
by depression in both the amplitude and rate. These changes are 
due to a narcosis of the respiratory center. 

The salicylates are used to produce a degree of germicidal action 
within the body, and their presence is specifically detrimental to the 
growth and development of the species that lead to the production of 
rheumatism, in which disease the salicylates have their greatest thera- 
peutic application. 



I. Internal Secretions. 

CHAPTER XXXI. 

INTEENAL SECEETIONS OF THE THYEOID AND 
PAEATHYEOID GLANDS. 

General Introduction. 

The internal secretions are denned as those substances which are 
produced in the body by special glands or gland-like structures and are 
discharged into the lymphatics or the circulation, ultimately in some 
way to influence metabolic processes in other tissues of the body. 
As a matter of fact, all the tissues elaborate materials either pure 
wastes on the way to elimination or intermediary products, which 
may be further oxidized, and therefore influence reactions in other 
parts of the body. Strictly speaking, the waste products are not 
considered in the class of internal secretions. The term is rather 
limited to materials which have more specific relations to the func- 
tions of other parts, relations that are drug-like in character. 

The manner in which internal secretions act in different organs 
has been under discussion for many years, and it can scarcely bo 
claimed that the matter is at present fully determined. The two 
leading hypotheses are: First, the theory that the secretion removes 
or renders inert some toxic substance of the body, and second, the 
theory that the internal secretion contains some specific substance 
which is necessary to the normal reactions occurring in other parts 
of the body. The former has been gradually displaced until at the 
present time it is practically abandoned. Those internal secreting 
glands and organs which produce substances that have been isolated 
and chemically identified by their physiological reactions in the body, 
have been specific enough to bring them within the second class. 
One need only to mention the active epinephrine from the suprarenal 
body as an example. 

An ideal internal secretion therefore would be one to which the 
tissue of some part of the body has become biologically adapted so 
that its normal function depends on the presence of the secretion. 
The general physiological assumption is that such internal secretions 

248 



HISTORICAL AND CHEMICAL 249 

contain a particular and more or less specific substance. To sub- 
stances of this class Starling 1 has applied the name hormone. 

Of the glands that are known to produce internal secretions, only 
a few have had the specific hormone identified. In fact, only two 
glands, the thyroid (with the parathyroid) and the suprarenal, have 
had their hormones isolated and identified chemically. However, we 
may confidently expect as a result of further investigation that addi- 
tional hormones will ultimately be isolated and their functions more 
specifically circumscribed. 

The subject of internal secretions is at present one w T hich concerns 
the borderland between Physiology and Pharmacology. This is un- 
doubtedly due to the fact of our incompletely developed knowledge 
of the actions of the hormones produced by these glands. That the 
subject will become more and more intensely vital to pharmacology 
is self-evident, hence its introduction in this discussion at the present 
time. 

The organs which produce internal secretions form a rather ex- 
tensive list, as follows: Thyroid, parathyroid, hypophysis, thymus, 
suprarenal cortex, suprarenal medulla, chromaffme tissue, pancreas, 
liver, kidney, duodenal mucosa, also different portions of the repro- 
ductive organs and reproductive tissues, including the testis, ovary 
(i.e., the Graafian follicle, and especially the corpus luteum), placenta, 
and fetus. 



A. 
THE THYROID AND THYROIODIN. 

I. 

Historical and Chemical. 

The thyroid glands, apparently including the parathyroid, have 
been shown to contain the iodine compound, which was isolated in 
1895 by Baumann. 9 This substance he purified and analyzed, and 
found that it contained as much as 9.3 per cent, of iodine (0.01 to 0.9 
per cent, of the dry weight of the human thyroid). Baumann's 
thyroiodin is readily soluble in dilute alkalies, but insoluble in acids. 

Starling, Erneal EL: Croonian Lectures, 1905. Also Lancet, Pt. 2, p. 579, 1905. 
1 Baumann, E.: Boppe-Seyler'a Zeiteohrifi fUr PhysiologUohe Chemie, Vol. 
XXL, p. 319, 1895-96. 



250 INTERNAL SECRETIONS OF THE THYROID 

It contains from 0.4 to 0.5 per cent, of phosphorus. Thyroiodin has 
been found in both the thyroid and parathyroid glands, though some 
question still exists as to the accuracy of the determinations for the 
parathyroids. 

II. 

Outline of Pharmacological Action. 

1. The thyroid extracts and thyroiodin produce changes in me- 
tabolism especially affecting the nervous system and the oxidative 
processes. 

2. The elimination or removal of the secretion deranges normal 
metabolism, especially of the nervous tissues. 

III. 

Details of Pharmacological Action. 

i. The effects of the removal of the thyroids. — The establish- 
ment of the function of the internal secreting glands in general has 
been no easy task. Of the earlier experiments in this field the most 
satisfactory results have been given by two methods. First, that 
which depends upon the disturbance of bodily functions after the 
removal of the gland, and second, the changes in function observed 
upon administering extracts of the gland. In the case of the thyroid, 
the later studies have shown that many of the brilliant earlier works 
were vitiated by a failure to recognize the presence of the parathy- 
roids. Gley x called attention to the extreme importance of the 
parathyroids, a point of view that has been fully confirmed since. 
Vincent and Jolly 2 state that the removal of all four parathyroids, 
as well as the thyroids, is not necessarily fatal. Although a fatal 
outcome usually follows, such is not due to surgical injuries to the 
surrounding structures, hence must be attributed to the loss of the 
glands. If the thyroid is removed, the parathyroids apparently are 
capable of replacing to some extent the characteristic thyroid struc- 
ture, a deduction based on the change in histological appearance, 
including the development of colloid. The removal of the thyroids 
is characterized by a marked myxedema, a condition that also char- 
acterizes certain thyroid diseases. The removal of the parathyroids, 
on the other hand, generally leads to the early death of the animal, 

1 Gley: Comptes Rendus de la Socie'te' de Biologic, p. 843, 1891. 

2 Vincent and Jolly: Journal of Physiology, Vol. XXXII., p. 651. 






ENGRAFTING OF THYROID TISSUE 251 

preceded by very characteristic nervous muscular disturbances de- 
scribed under the name of thyroid " tetany." 

Edmunds has observed thyroid myxedema in monkeys, though 
this was not confirmed by Vincent and Jolly. The fact that the two 
internal parathyroids are deeply imbedded in the lobes of the thyroid 
and are highly vascular makes it exceedingly difficult to remove the 
one gland without interference with the other. This statement ap- 
plies in explanation of certain criticisms which have arisen as re- 
gards the source of the thyroiodin. 

2. The engrafting of the thyroid tissue. — In the operative 
work for the removal of the glands it has been noticed that 
if an exceedingly small remnant is left behind, the usual symp- 
toms do not follow. In other words, a remnant is capable of taking 
care of the function of the whole gland. This fact has led to at- 
tempts to engraft thyroid tissue in other parts of the body. These 
attempts, though at first unsuccessful, have finally succeeded. Mc- 
Pherson records beneficial results in man from transplantation of 
thyroid to the extent that symptoms of myxedema disappeared after 
operation and had not returned within three years. The transplanted 
thyroid tissues are usually absorbed, but if they " take " and the 
vascular supply becomes well established, it is assumed that the 
normal production of the active thyroid hormone occurs. 

3. The interrelationship of the thyroids and the parathyroids. — 
Numerous experiments point to an intricate functional relation be- 
tween the thyroids and the parathyroids. The most importance rests 
upon the physiological fact that the removal of the parathyroids is 
far more fatal than the removal of the thyroids, and that the loss of 
either of the glands leads to a different type of functional defect from 
that which characterizes the loss of the other. The embryological 
and histological observations show that the parathyroids take on the 
structural characteristics of the thyroids after the removal of the 
Latter, showing a close relationship between the two. The iodine 
content varies greatly in the thyroid tissue. There is, according 
to GUey, many times more iodine in the thyroid tissue than in the 
parathyroid. However, Mendel ' has confirmed the presence of iodine 
in the parathyroids. The facts observed have led to the view that the 
parathyroids prepare the iodine compound, which is later stored in 
the tissue or colloid of the thyroid. This view of Gley has been 
strengthened by the observation that there is a disturbance of iodine 
metabolism when the thyroid is extirpated. 

1 Mendel, L. B.: The American Journal of Physiology, Vol. III., p. 203, 1900. 



252 



INTERNAL SECRETIONS OF THE THYROID 



4. Observations from the feeding of the thyroid tissue and of 
thyroiodin. — Experimental procedure demonstrated the stability 
of the thyroid hormone, both to digestion and to heat, even before 
the isolation of thyroiodin. Now both thyroid tissue and the thyro- 
iodin are given by way of the mouth. Thyroid substance introduced 



ji.thffr.M— 



tfiym.m- 




Fig. 63. — Diagram to show the branchial origin of certain internal secreting glands. 
I, II, III, IV, the respective branchial arches ; thyr., thyroid ; p. thyr. } parathyroids ; 
thym., thymus ; pb. &., post-branchial body, which in development becomes imbedded 
in the thyroid. From Vincent and Jolly. 

by this channel has the same physiological effects that occur from 
engrafting the tissues. It would seem that the active hormone is 
not only not destroyed in digestion, but is absorbed and can reach the 
circulation and thus influence metabolism in the usual way. Thyro- 
iodin purified by the method of Baumann is recommended as a substi- 
tute for the thyroid tissue. While the influence which it has on 
metabolism seems to be the same, it has not always proved to act 
with the same vigor and efficiency as the tissue of the gland itself. 
Certainly iodine, as such, does not take the place of this organic 
thyroiodin compound, hence it is assumed that the function of the 
gland is to build up the thyroiodin compound, thus getting the iodin 
in an available form for the use of other tissues. 

In confirmation of the point just made, Marine has found that 
enlarged thyroids with a diminished quantity of thyroiodin present 
tend to return to the normal upon feeding of iodine. After iodine he 
found an increased percentage of thyroiodin present in the gland. 
In other words, as Marine expresses it, " iodine administered to dogs 



DETAILS OF PHARMACOLOGICAL ACTION 253 

with hyperplastic thyroids has a physiological action like the desic- 
cated thyroid, i.e., it rapidly reduces the body weight, while iodine 
administered to normal dogs does not." 

B. 

PAKATHYKOLDS. 

We have already stated the fact that the removal of the parathy- 
roids without interference with the thyroids leads to grave symp- 
toms and usually the death of the animal, though, as was stated above, 
Vincent and Jolly showed that death did not always follow. 

5. Systemic phenomena following removal of parathyroids. — 
In a word, the typical symptoms following the removal of the parathy- 
roid is expressed by the term " tetany." The animals show a pro- 
gressive development of nerve and muscular incoordination, ending in 
tetanic spasms and death. There are evidences of central nervous 
disturbances expressed in the restlessness, anxiety, and mental stress 
as interpreted from operated dogs. 

6. Disturbances of metabolism after parathyroidectomy. — W. 
F. Koch x has recently examined the effects of parathyroidectomy on 
dogs from a physiological chemical standpoint. He found the pres- 
ence of methylguanidine in the urines of six different animals inves- 
tigated, as well as certain other purine derivatives. After parathy- 
roidectomy, Koch's dogs died in four or five days, exhibiting the 
usual muscular and nervous spasms, i.e., " tetany." 

The chemical showing was supplemented by a study of the histo- 
logical changes in different tissues. Material from the liver, kidney, 
and brain showed cellular chromatolysis as a constant characteristic. 
" The brain sections showed cells in the motor areas with partial 
loss of Nissl substance and typical tetany nuclei. Various degrees 
of chromatolysis were also observed in these nuclei." He found 
degenerating epithelial cells in the intestinal tract, the nuclei of 
which were converted into solid, deeply staining clumps. 

The hepatic cells " showed advanced fatty degeneration of the 
protoplasm. The nuclei of large areas had disappeared entirely in 
places where the cell form was fairly well preserved." In the liver 
of certain of his animals there was only a diffuse chromatolysis. In 
the kidney there was " congestion and hemorrhage in the cortex, 
some anemic and others congested medulla?. Some glomeruli had lost 
Bowman's capsule." There was also epithelial degeneration. 

1 Koch, \Y. F.: The Journal of Biological Chemistry, Vol XV., p. 43, 1913. 



254 INTERNAL SECRETIONS OF THE THYROID 

Physiologically the dogs were restless and easily excited. The 
limbs later " showed tremors, especially after slight exertion." Still 
later the animal exhibited mild convulsions with rigid and extended 
limbs. In the final stages before death, there were " severe tetany 
and clonic convulsions," and at times salivation and Cheyne-Stokes 
breathing. 

7. The theoretical significance of Koch's observations. — The 
discovery of toxic bases, methylguanidine and other guanidine bases, 
in large quantities in the urines of parathyroidectomized dogs has 
led Koch to believe that " the parathyroid secretion, therefore, ap- 
pears to be concerned with anabolic processes closely related with 
the building of nucleins." Koch comes to this conclusion from the 
pathological appearance of the tissues, i.e., their chromatolysis, along 
with the finding in the excretion of the wastes undoubtedly derived 
from nuclein metabolism. It is generally conceded that the metabol- 
ism of chromatin is a nuclear function. The failure of different 
functions in the parathyroidectomized animals drives the tissues to 
protein starvation and " nuclein atrophy." This is peculiarly sug- 
gested by the extensive coagulation of the blood in the blood-vessels, 
and indicates the presence of free nucleic acid in the circulation. 

In what manner the absence of the parathyroid leads to this 
marked tissue disruption remains yet to be explained. The work of 
Koch brings us much nearer the solution of the problem, since it 
gives for the first time an explanation of the nature of the change in 
metabolism. It has not yet been shown that the artificial supply of 
parathyroid substances will alleviate this condition. 



CHAPTER XXXII. 
THE PITUITARY GLAND AND THE HYPOPHYSIS. 

I. 

Anatomical. 

The pituitary anatomically consists of three parts: (1) the pars 
anterior, or pituitary gland proper, (2) the pars intermedia, which is 
distinctly separated from the anterior and more closely related to 
(3) the pars posterior or hypophysis proper. The anterior and inter- 
media portions are derived from the epithelium of the roof of the 
mouth, while the hypophysis is an evagination of the brain cavity. 
That these two structures produce internal secretions or hormones can 
no longer be doubted, though a chemically distinct hormone has been 
isolated from neither. 

II. 

Outline of Pharmacological Action. 

1. The evidence indicates that the pituitary increases oxidation 
and stimulates the growth of the connective and skeletal tissues. 

2. The internal secretion of the pituitary has a reciprocal rela- 
tion to the development of the essential sexual organs. 

3. The hypophyseal extracts {posterior lobe) produce an increase 
in the force of the heartbeat, the contractions of the smooth muscle 
structures, such as the bladder, uterus, and intestine, increase in car- 
bohydrate metabolism, and an increase in certain secretions. 

III. 

Details of Pharmacological Action. 

A. Pituitary Gland. 

i. The changes in metabolism following the removal of the 
pituitary secretion. — Our knowledge of the pituitary is largely de- 
rived through observation of changes in function or in growth, which 
accompany atrophy of the gland or its removal on the one hand, or 

255 



256 THE PITUITARY GLAND AND THE HYPOPHYSIS 

the contrary changes that are associated with hypertrophy of tha 
gland, or with the injection of its extracts. 

As in the case of the interrelation of the thyroid and parathyroid, 
so here the mechanical difficulties of separating the pituitary from 
the hypophysis have contributed largely to the difficulties in deter- 
mining the function of these two important structures. 

Recently, through the skill of such investigators as Paulesco, and 
of Cushing, operations have been performed, removing the anterior 
or the posterior lobes independently. When the pituitary gland proper 
is removed, as a rule death soon follows. This can now be recorded 
as an established fact. The inference offered in explanation is that 
the disturbing cause is the elimination of the interstitial secretion of 
the gland. 

The removal of large portions of the pituitary gland, and in some 
cases of the entire gland, in early life is survived (three-months-old 
puppies). However, there is a restriction in the usual growth of the 
body with certain changes in the general tissues, particularly in the 
acquirement of fat. The reproductive organs also fail to develop and 
show atrophic changes. Metabolism experiments on such animals 
show a diminution of oxidative processes, especially characterized by 
a lesser amount of carbon dioxide. 

2. The administration of pituitary. — Numerous attempts have 
been made to resupply the pituitary, experimenting along the lines 
which have long been practiced in the case of the thyroid. Schaefer, 
and later Cushing, have published numerous observations. Both 
have fed pituitary and reported that the symptoms which follow the 
removal of the gland are delayed by this treatment, a fact, however, 
which has not been always supported. Cushing, in particular, finds 
that patients suffering from diminished pituitary secretion are bene- 
fited by the pituitary extracts. 

Transplantation of anterior lobes was performed by Cushing in 
an animal from which this lobe had been removed. This delayed 
for several weeks the fatal results that usually follow the operation. 

3. Clinical evidences from atrophy and hypertrophy of the 
pituitary. — It has been long known that certain individuals have 
manifested retarded development on the one hand and an extraordi- 
nary development, acromegaly, on the other. The explanation of 
these exceptional cases seems now definitely traced to the variation in 
development of the pituitary gland. A hypertrophied gland so stim : 
ulates the growth of the bony tissues as to produce an enormous 
size of the body. On the other hand, atrophy of this organ leads 



HYPOPHYSIS 257 

to the opposite result, namely, infantilism. It is in this latter class 
that Cushing has attempted to secure benefit by giving the gland in 
routine medicinal treatment. 

4. The interrelation of the pituitary and other organs. — There 
is a reciprocal relation existing between the pituitary and the thyroid. 
The operative interference with the thyroid, as by removal, is asso- 
ciated with a vigorous ' ' taking on " of its function by the pituitary, 
as manifested by the greater size of the latter. On the other hand, 
a much more important interrelation exists between the development 
of the pituitary and the sexual gonads. This has already been men- 
tioned. In dogs, the development of the ova and spermatogenesis are 
markedly delayed by removal of the gland, whereas an accelerated 
sexual development has marked certain cases of giantism. 

B. Hypophysis. 

1. Influence of the hypophysis on the functions of nerve struc- 
tures. — The hypophysis bears a less crucial relation to the body 
functions than does the pituitary. The extracts of the gland, however, 
have been demonstrated to produce definite changes in the physio- 
logical function of organs of the circulatory system, of the digestive 
tract, and of the uro-genital system. 

2. The heart. — Howell first clearly demonstrated that the pos- 
terior lobe, which he called the infundibulum, has a marked influence 
on the circulatory apparatus. The injection of the extracts produces 
a rise of blood-pressure, with an initial acceleration of the heartbeat. 
This was followed by some depression of blood-pressure, and there 
was a marked slowing of the heart rhythm. It has been shown lately 
that the stimulus to the heart action probably rests on stimulation 
of peripheral augmentor nerve structures. 

3. On smooth muscular structures. — The digestive tract is stim- 
ulated to increased contraction by the intravenous injection of hypo- 
physeal extracts. The uterus undergoes excitatory contractions prob- 
ably through the stimulation of nerve structures of the inferior 
in. scnteric paths. These paths also supply nerve fibers to the urinary 
1)1 a elder, in which increased contraction is also noted. 

4. Hypophysin. — The name " hypophysin " has been given to the 
active principle or extract of the hypophysis or posterior lobe. The 
true source of this active material is not altogether clear, since the 
colloidal material found in the pars intermedia and to some extent 
in the hypophysis may be of extraneous origin so far as the hypo- 



258 THE PITUITARY GLAND AND THE HYPOPHYSIS 

physis is concerned. It is generally conceded- that the secretion of 
the pituitary is distributed into the spaces of the pars intermedia 
and the pars intermeninges. It is possible that this secretion may 
pass into the hypophysis to some extent. By this view one may readily 
understand the fatal outcome of the removal of the pituitary in that 
it removes the active tissue forming this internal secretion. The 
removal of the hypophysis would not interfere with the development, 
but only with the distribution of the pituitary secretion. 






J. Irritants and Counter Irritants. 

CHAPTER XXXIII. 

THE BACTERIAL TOXINS. 

General Introduction. 

There are a great many drugs and materials of general pharmaco- 
logical interest, the importance of which is chiefly bounded by some 
local and special action, i.e., a local toxic action to protoplasm, which 
is associated with more or less profound secondary changes. Some 
of these lead to a quick dissolution of protoplasm, hence are corrosive 
in nature. Certain of these drugs are discussed in other connections, 
i.e., the caustic alkalis and the mineral acids. In this entire group, 
even with drugs in which the caustic action is very intense, some de- 
gree of their influence generally calls forth a response in the tissues 
characterized by the process of inflammation. Such drugs are called 
Irritants. 

The number of chemicals and other agents which produce injury, 
therefore irritative processes, is enormous, hence it will conserve the 
time of the reader if the principles underlying their action are briefly 
explained and illustrated by typical members of the series. 

Irritants may act on any and all tissues of the body or on special 
structures only. Therefore, the groups of irritants, which we shall 
emphasize, are of necessity somewhat arbitrarily chosen. They are of 
four great classes : 

1. The Bacterial Toxins, reacting on any and all tissues of the 
body with which they come in contact, but often quite specific in the 
case of particular toxins. 

2. The Skin Irritants, those drugs generally recognized because 
they are peculiarly adapted to affect the relatively impermeable ex- 
ternal skin. 

3. The Vegetable Cathartics, that large group of irritant prepara- 
tions of vegetable origin, which react on the lining of the alimentary 
canal and which are used in clinical medicine for the production of 
catharsis. 

259 



260 THE BACTERIAL TOXINS 

4. The Counter Irritants, those drugs primarily of groups 1 or 2, 
which, in a certain intensity of action, produce marked secondary 
changes in other parts of the body. Reactions of this class are 
known in medicine as counter irritations and the causal agencies 
as counter irritants. 

I. 

Historical and Introductory. 

It is difficult to condense into a few words the essential factors 
in the discoveries and study of the influences of bacteria and bacterial 
products on the living organism. This topic is at the foundation of 
our study of the Germ Theory of Disease, and its fundamental impor- 
tance permeates a number of essential medical subjects. Bacteria 
growing in the living body may in themselves through mechanical 
factors induce stages of inflammation. However, this is quite a sec- 
ondary influence in contrast with degrees of change induced by what 
we now know to be chemical substances liberated by such bacteria dur- 
ing their life cycle. 

Bacteria induce chemical changes in proteins, setting free toxic 
disintegrative, i.e., putrefactive substances. These substances are 
basic in character and have received the class name ptomains. They 
also produce synthetically and liberate in solution in the circulating 
fluids a different class of non-basic poisonous substances, which are 
called toxins. Certain bacteria finally at the time of disintegration 
after their death liberate yet a third class of toxic materials similar 
in character to the toxins but less soluble, known as endotoxins. 

The influence of putrefactive products developed in decaying flesh 
was first experimentally examined by the physiologist, von Haller, in 
the eighteenth century. In the middle of the nineteenth century 
Panum examined these ' substances for their physical and chemical 
properties, and gave us some notion of their toxicity by experiments 
on dogs. 

Breiger in the period from 1882-1886 isolated and determined 
the chemical context and composition of a number of toxic substances 
derived from decaying meats. Among others are trimethylamin 
N(CH 3 ) 8 and mytilotoxin C G H lr ,N0 2 , from the poisonous mussel. 
The non-basic poisonous substances, which we now call toxins, were 
in Brieger's scheme of classification named toxalbumins. These toxins 
have been extensively studied, but not chemically isolated. Toxins. 
as above defined, do not cover all the toxic substances resulting from 



THE NATURE OF IRRITANT ACTION 261 

bacterial growth. It is found that the dead and disintegrating cell 
bodies of certain bacteria contain highly toxic but less soluble ma- 
terials than the toxins. These are the endotoxins. Neither have the 
endotoxins been chemically isolated. 

When toxic bacteria are growing in the living body, or in fact, 
when the toxins derived from their growth are injected into the circu- 
lation, the body tissues are stimulated to produce chemical substances 
which are neutralizing to the toxins. These are the antitoxins first 
described by Behring and Kitasato 1 in 1890. The formation of anti- 
toxins does not include all the protective processes induced by toxins 
in the animal body. The studies of Pfeiffer in 1894 on immune cholera 
serum developed the fact that the serum contained a destructive 
agent, which we now know under the name bacteriolysin. Without 
going into detail, attention may be called to the agglutinins and 
precipitins, which, together with the lysins and antitoxins, contribute 
to the immunity of an animal against bacterial invasion. 



II. 

Details of Pharmacological Action. 

i. The nature of irritant action. — An irritant, mechanical or 
chemical, may be defined as an agency which produces a local injury, 
to which the tissue or tissues react by a reconstructive process, the 
stages of which constitute acute inflammation. That the drugs of 
the so-called " Irritant " series possess toxic action for most tissues 
of the body is a well-known fact and does not need elaborate discus- 
sion, but the character of the action of the irritant calls for detailed 
explanation. Chemicals are by no means the only agencies for the 
production of irritations leading to inflammation. One of the simple 
causes of the inflammatory process is ordinary mechanical injury, 
i.e., traumatism. The redness or the blisters from milder burns are 
responses to heat irritation. Excess! ve nerve reactions may pro- 
duce similar end results. Bacterial growths, certainly of the infec- 
tious and often of the saprophytic type, sel up inflammations, due 
chiefly to chemicals in this case, however. The products of bacterial 
growth, toxins, are typical irritants, though the discussion of their 
action because of the great importance in relation to the cause of 

1 Behring and Kitasato: "Ueber das Zustandckommen der Diphtherie- 
Immunjtal und der Tetanus-Immunitat bei Thieren," Deutsche mediciniache 
Wochenaohrift, p. 1113, 1890. 



262 THE BACTERIAL TOXINS 

disease is now studied in more advanced detail in other medical rela- 
tions. The response to irritation, i.e., inflammation, may, in fact does, 
occur in all parts of the body and in all tissues. In the broader 
sense it is obvious that no logical boundary between susceptible and 
non-susceptible tissues can be drawn. But in the restricted sense, in 
which the term is more often used, pharmacological irritants are 
primarily either skin irritants or irritants of mucous membranes. 

2. The inflammatory process a physiological response to irri- 
tant action. — The basic principle to consider in the study of irritants 
is the fact that they are injurious to protoplasm of all kinds. Of 
course different drugs of the various classes injure in different 
degrees, therefore the degree of the response which is produced will 
depend on the relative toxicity of the drug as such, or on the rela- 
tive toxicity as influenced by its time of contact, or by its concentra- 
tion. The protoplasmic factor is the sensitiveness of the tissue to 
local injuries. Of all the tissues, the epidermal and the connective 
tissues are especially responsive to toxic actions of this class. Toxins 
are only chemicals of a special class. 

The mild action of practically all irritants can scarcely be dis- 
tinguished from that of physiological stimulation, which indeed it is. 
There is no sharp line to be drawn between the physiological meaning 
of the two terms. If any distinction is to be made, it is the tendency 
to apply the term ' ' irritant ' ' to causes of reactions which are in the 
nature of general responses of protoplasm, or perhaps it would it 
would be better to say responses of general protoplasm. The word 
" stimulus " in contradistinction to this use is applied to causes of 
reactions expressed through the more highly differentiated organs and 
tissues, and by the characteristic power which the special tissue pos- 
sesses by virtue of its differentiation. To illustrate further, the stimu- 
lation of a muscle calls for the characteristic contraction. This may 
be with or without a general change in the protoplasm of the tissue. 
Irritation applied to a muscle, while it may lead to contraction, has a 
tendency to produce basic changes in the protoplasm itself, which, if 
carried far enough, may lead to disintegration with destruction of the 
tissue. Speaking generally, the incipient irritative process, whether it 
be produced by drugs or other injurious agencies, is of a stimulative 
nature. But the reaction tendency in general is that of cell growth, 
cell proliferation or cell death, rather than that of energy liberation. 
If the irritation be carried further, then there is injury to the local 
tissues, which is characterized by definite changes following in a well- 
described cycle. These are the changes of inflammation that have 



THE IRKITANT ACTION OF BACTERIA 263 

been so admirably presented by Adanii, 1 Councilman, 2 and others. 

In the section on skin irritants there is presented a detailed de- 
scription of the process of inflammation as it occurs typically in the 
skin. This detail should be consulted and is presupposed in connec- 
tion with the discussion that immediately follows on the irritant action 
of the bacterial toxins. 

3. The irritant action of bacteria and bacterial toxins. — Of all 
the irritative and toxic agents that affect the human body, those of 
most practical importance are the bacteria and the toxins, lysins, etc., 
resulting from their presence, growth, and development. Not all 
micro-organisms have an irritant action on the human body. Many 
forms of bacteria inhabit the skin, the mouth, and different divisions 
of the alimentary tract without producing deteriorating effects on 
those structures, at any rate not under ordinary conditions. Certain 
bacteria are in marked contrast, the pathogenic bacteria. These are 
peculiarly destructive to the tissues of the human body. 

A great variety of conditions influence and control the rate and 
character of the invasion of the human body by pathogenic bacteria. 
Among those that should be mentioned are variation in individual 
susceptibility, variation in the defensive powers of the individual at 
different times, the mode of invasion, and the relative virulence of 
the particular organism concerned. Not all tissues of the body are 
equally resistant to the invasion of any particular pathogenic bacte- 
rium. As a rule, the most highly differentiated tissues are the most 
susceptible, while the tissues of more generalized function, such as 
the connective tissues, are the least susceptible. 

"When pathogenic bacteria invade the body they produce, as a 
result of their growth and development, materials that are highly 
irritant and peculiarly toxic to the human body. These substances 
are the toxins. It may happen, however, that the active irritants 
are not liberated directly by the living bacteria, but are set free upon 
the destruction of those bacteria that have run their life cycle. These 
substances have received the name endotoxins. In either case the in- 
jurious agencies come from the presence of the bacteria, and are 
strongly disturbing to the normal functional reactions of the proto- 
plasm of the tissues of the host. The liberation of the toxins resulting 
from the growth of the colony of invading bacteria of course takes 

1 Adami, J. George: Chapter on "Inflammation," Principles of Pathology, 
2nd edition, New York, Vol. I., p. 413, 1909. 

2 Councilman, Wm. T. : Article, "Inflammation," Buck's Reference Handbook 
of the Medical Sciences, Vol. V., p. 1, 1902. 



264 THE BACTERIAL TOXINS 

place primarily at the growth center, the focus of invasion. They 
readily diffuse into the blood stream and the surrounding lymph 
channels, thus reaching a general systemic distribution. We find, 
therefore, that the toxic action of the toxins is both local and general 
in nature: local, because of the more intense concentration of toxin 
resulting in local inflammation ; general, because, of the ready distri- 
bution of toxin through the circulation and its contact with all the 
tissues. 

Bacterial toxins are, in the last analysis, strongly irritant agencies. 
They produce the cycle of irritation and inflammation, running a 
course which is more or less characteristic for the different tissues, 
and for the different toxins. The interrelations have been strongly 
put by Adami, 1 when he used the action of toxins to illustrate de- 
grees of irritation as follows: — 

' ' Reverting to the differing degrees of irritation, we may draw up 
a working scale of, for example, toxins. Certain of these, which we 
will for the moment designate degree A, are so strong that they kill 
at once a certain cell with which they come in contact ; others, degree 
B, are not strong enough to kill instantly, but they so injure the cell 
that it enters at once into the stages we call cloudy swelling, granular 
degeneration, or whatever name we employ, and finally dies; this 
process we call bio-necrosis. Yet others, degree C, injure the cell so 
that it enters this condition of successive ill-being, but finally re- 
covers; this is not exactly bio-necrosis, but, if we dare coin a word 
for present use in this chapter, it might be said that the toxin is 
bio-necrescent, that is, tending to bio-necrosis. Finally, other toxins, 
yet weaker, degree D, irritate the cell within the limit of its reactive 
powers, but without exhausting the same, and its irritation is shown 
by reproduction, by phagocytosis of chemiotaxis, or any other func- 
tion we can attribute to the cell that is ' roused.' And this is true, 
not only in regard to different toxins, but in regard to different de- 
grees of concentration of the same toxin. We have to recognize, in 
short, the law that the agent, which in high dilution or small quantity 
acts as a stimulant to the cell, becomes in greater concentration a 
poison to the same. 

1 ' It will be at once evident that, in the kidney, for example, toxic 
blood may severely injure a tubule cell (degree B), yet may not be 
able to do more than rouse the connective tissue to reproduction 
(degree D). Every cell of the body that comes within the ' sphere 
of influence ' of a toxin reacts, in some degree thereto, degree A, B, C, 
1 Adami, J. Geo.: Keen's Surgery, Vol. I., p. 191, 1906. 



THE CHARACTERISTICS OF TOXINS 265 

or D, and this applies, not only to fixed cells, but to every lymphocyte, 
leukocyte, or wandering tissue cell whose business calls it into the area 
of irritation at the time; the result of any inflammation depends, 
therefore, on the sum total of these million tiny problems, and the 
total determines whether the balance is in favor of or antagonistic 
to the body." 

The broad subject of bacterial toxins and their action has, how- 
ever, assumed such importance and has become so specialized in rela- 
tion to disease that the custom has arisen of treating this subject 
in special texts and monographs, 1 hence the very brief discussion 
presented in this relation. 

4. The characteristics of toxins. — The toxins are admittedly 
chemical substances, although we know very little of their detailed 
chemical nature. The great mass of our knowledge of the nature of 
toxins is derived from the influences of these substances on physio- 
logical processes. One point that has come out in their study is that 
toxins diffuse through animal membranes with great difficulty. Their 
action on living protoplasm is more or less specific and in this regard 
there is some comparison between the toxins and the toxic influence 
of certain proteins, that is, they are capable of stimulating the tissues 
to the production of antibodies. The toxins are nearly all destroyed 
by enzymes, by heat, and, in some cases, by light. Chemical sub- 
stances of analogous composition are found in both the animal and 
the plant world. For example, the venom of poisonous snakes and 
of poisonous insects reacts in a way quite similar to the toxins of 
bacterial origin. In the plant world the poisonous ricin is possibly 
also of similar nature. At any rate, it produces similar reactions on 
protoplasm. Recently some most interesting observations that throw 
light on the nature of toxins have been made on isolated by-products 
of bacterial putrefactory changes. Barger and Walpole 2 isolated 
three pressor principles from putrid meat, namely isoamylamine, de- 
rived from leucine, phenylethylamine, derived from phenylalanine, 
and parahydroxyphenylethylamine, derived from tyrosine. These 
amines have many of the physiological characteristics of the toxins, 

1 See Vaughan and Navy: Cellular Toxins. Philadelphia, 1902. 

Schorer: Vaccine and Serum Therapy. St. Louis, 1909. 

Oppenheimer: Toxin and Antitoxin. Jena, 1904. 

Ehrlich: 'csa mm cite Arbeiten zur Immunitdtsf 'orach. Berlin. 1904. 

Also works on bacteriology, pathology, and on infectious diseases. 
■Barger, G., and Walpole, G. S.: Journal of Physiology, Vol. XXXVIII., 
p. 343, 1909. 



266 THE BACTERIAL TOXINS 

although the isolation of toxins has not been chemically made and we 
cannot as yet be sure that they are of the same class. At least one 
may consider these purified amine bodies as showing interesting 
analogies as between the pharmacological action of the amino-acids and 
the toxins. This group is of further interest in that it has been lately 
shown by Barger and Dale that the same active principles are present 
in the fungus ergot. 

5. The type of toxin action. — We get our best conception of 
the nature of the toxin reaction by comparison of the reactions in the 
chemical field. Certain complex organic chemicals have a multiplicity 
of side chains to which other substances may be chemically bonded. 
This conception has been applied to the toxins of unknown chemical 
composition by Ehrlich in his Side Chain Theory of the action of 
toxins and antitoxins. As early as 1885, Ehrlich, in discussing the 
nature of cell nutrition, expressed the opinion that the great variety 
of nutrient substances were assimilated by a method of attachment 
or bonding of these substances to the complex of the "protoplasm. 
In short, protoplasm by means of its numerous side chains was able 
to chemically attach to itself the materials entering into its nutrition. 

This conception applied to the action of toxins resulted in the 
development of Ehrlich 's Side Chain Theory, a theory that wonder- 
fully adapts itself to the explanation of the great variety of general 
biological and chemical processes as well as those physiological 
processes involved in toxic action. 

6. Toxins stimulate the tissues to produce antitoxins. — The 
presence of toxins in the body affects the protoplasm of the tissues 
in one highly important way, namely, it stimulates the production of 
substances which have the general effect of neutralizing or warding 
off the toxic action of the toxins themselves. The tissues, in other 
words, produce chemical substances which are antagonistic to the 
toxins. These are the antibodies and are called antitoxins. Anti- 
toxins were first described by Behring and Kitasato in 1890. These 
men produced immunity in animals against tetanus by injecting the 
serum from certain actively immune animals. The presence of a 
poisonous amount of toxin which, if it ran its course in the body, 
would result in the destruction of the life of the organism as a 
whole is rendered relatively innocuous, provided a sufficient quantity 
of antitoxin can be developed to take care of the toxin. This is the 
principal factor in the self-limitation of many of the infectious dis- 
eases. The development of antitoxins by the body in response to the 
presence of the toxic bacteria is called active immunization. Medi- 



SPECIFICITY OF TOXINS 267 

cine has now reached a stage of development in which science has 
been able to produce antitoxins in usable quantity by injecting certain 
animals that are relatively immune with the pathogenic bacteria for 
which the antitoxin is specific. Such serum, rich in antitoxin, when 
introduced into the body of a person also exerts a restraining influ- 
ence on the growth or invasion of pathogenic bacteria. This method 
of securing protection is known as passive immunization. 

7. Specificity of toxins. — Without discussing the matter in detail, 
attention may be called to the fact that many of the toxins are 
notably specific or selective in their reactions among the tissues of the 
body. As a single example may be mentioned tetanus toxin which 
attacks nerve tissue. If brain tissue be mixed with a tetanus toxin 
solution and the brain tissue be separated off, it carries with it the 
toxin. 

When the human body has been attacked by certain bacteria, for 
example tubercle bacilli, the reaction in the tissues leads to a change 
in the susceptibility of those tissues to the products of the growth of 
the bacilli. The tuberculin skin test is an example in this case. The 
epidermis of the tuberculous patient is more susceptible to the irritant 
action of tuberculin than the skin of a normal person. This increase 
in susceptibility is great enough to give to the reaction of irritation 
a specificity which aids in the diagnosis of the disease. 

There is a close relation between the toxin and the antitoxin 
developed by the body under the influences of the toxin, a relation 
that is in this instance entirely specific. Each particular toxin 
stimulates the tissue to produce an antibody, which reacts with and 
neutralizes the toxin, thus eliminating, the latter from its poisonous 
influences on the body tissues themselves. An antitoxin developed in 
response to one toxin will not combine with a different toxin. In 
other words, the antitoxins are not interchangeable in antagonizing 
the toxins. One can find an analogy in the chemical field as between 
the reaction of chemical substances which have an affinity for each 
other, but not for chemicals of a different class. The development 
of antitoxins by the body is, therefore, a protective factor, a response 
of the tissues to the irritant and toxic action of the toxins. The 
reaction between the antitoxin and the toxin is, therefore, a reaction 
of distoxication. In other words, the toxin is rendered chemically 
inert by the ever present antitoxin. It is the presence of the anti- 
toxin in the blood and body fluids which seizes upon and fixes any 
entering toxin irritants and gives to the body the property of im- 
munity. 



CHAPTER XXXIV. 
IREITANTS OF THE EXTERNAL SKIN. 



I. 

Historical and Introductory. 

Numerous chemical groups, with a wide range of representation, 
induce inflammatory changes in the skin. These chemicals possess 
two properties, which adapt them to this type of reaction in the 
body, namely, a high degree of toxic influence on general proto- 
plasm and general solubility in the skin fats. The conventional 
members of this series are: — 

1. The essential oil group consisting of the volatile oils, often in 
solution in the tars and resins; 2. The mustard group containing 
glucosides which, on cleavage, liberate an irritant oil ; 3. The canthari- 
din group, consisting of soluble and highly irritant neutral bases; 
and 4. Forms of mechanical energy such as heat, etc. 

Turpentine serves as a type of the volatile oil series. This is a 
distillate from certain woods, especially the conifers, and contains 
a resin dissolved in essential oils. The various volatile oils belong 
to the benzine group, and contain numerous representatives of the 
terpenes with the formula C 5 H 8 or some multiple of this grouping. 
They are easily converted into cymene, which has the structural 
formula : — 

CH3/ Nch/ 

\ / \CI-I S 

Members of the genus Sinapis, the mustards, contain beside other 
substances, sinalbin, which is a glucoside, in combination with the 
oil of mustard. The plant also contains a glycolytic ferment. The 
pulverized seed of Sinapis alba when mixed with water ferments 
according to the following formula: — 



C H NSO 

30 42 2 2 15 

Sinalbin 
(non-irritant) 



H = C H ONCS + CHO+CHNO HSO 

2 7 7 ^ 6 12 6 16 24 6 4 

Water Oil of mustard Dextrose Sinapin sulphate 



Oil of mustard 
(irritant) 



Cantharidin is a very strong irritant derived from the dried 
beetle, Cantharis vesicatoria, of southern Europe. This material 

268 



OUTLINE OF PHARMACOLOGICAL ACTION 269 

contains the toxic substance cantharidin, C 10 H 12 O 4 . Cantharidin is 
slightly soluble in water, in alcohol, etc. There are a number of other 
materials, notably the toxicodendrol of our common American' poison 
ivy, which have similar irritant actions. 

Mechanical agencies such as heat are skin irritants. Heat, for 
example, may be applied in so many different ways and under such 
well controlled circumstances that it becomes one of the best of prac- 
tical agencies for inducing degrees of irritant action for therapeutic 
purposes. 

II. 
Outline of Pharmacological Action. 

1. Power to penetrate the corneal layer of the outer skin and 
produce varying degrees of toxicity to the underlying epidermal tis- 
sues, nerve endings, etc. Or, in the case of heat, power to produce 
direct mechanical injury and irritation. 

2. Power to produce counter irritant effects on account of the 
peculiar segmental nervous relations of the shin and the deep-seated 
organs. 

III. 
Details of Pharmacological Action. 

i. The permeability of the skin to certain irritants. — The gen- 
eral resistance of the external skin to large classes of injurious sub- 
stances renders it more or less immune to many agencies which would 
induce inflammation if brought into contact with unprotected parts 
of the body. This is primarily due to the relative impermeability of 
the skin to chemical agents. Members of the volatile oils and others 
of the chemicals mentioned above more freely penetrate the corneous 
coat of the skin and reach to the living epidermal cells and the der- 
mal structures below. In addition there are certain highly volatile 
chemicals, like chloroform, which are soluble in the skin and which 
if held in contact with it a sufficient length of time produce irritation. 
Under ordinary conditions the great volatility prevents the manifesta- 
tion of their irritant properties. Irritant substances, on account of 
their ready diffusibility through the corneous layer of the skin, or by 
virtue of their solubility in some particular constituent of the skin, 
can readily penetrate this otherwise impervious structure. These 
materials are injurious to protoplasm and set up changes which are 
described by the various stages of the process of inflammation. 

2. Stages of acute inflammation produced by irritation. — In- 
flammation of the skin is characterized by the development of redden- 



270 IRRITANTS OF THE EXTERNAL SKIN 

ing, swelling, heat, and pain, i.e., the " rubor, turgor, calor, and 
dolor ' ' of Celsus. There is naturally a varying degree of disturbance 
of the function of the part. It is a well established physiological fact 
that a very mild cutaneous stimulation generally, though not always, 
leads to a slight vascular constriction, i.e., a heightened vascular tone 
which in the skin leads to the external manifestation of pallor, etc. 
If, on the other hand, the stimulation is vigorous, approaching the 
painful, the response leads always to vascular dilation. 

Skin irritants produce more than simple stimulation, but we may 
expect the same physiological reactions from the mild local nerve 
effects of the irritants. These irritants act through a period of time 
and with increasing intensity. Hence the reaction on the circulatory 
system, while it may at the very first show vascular constriction, 
will later lead to marked dilation of the blood-vessels of the part 
affected. It is this process that especially characterizes the first 
stage in inflammation, namely, the reddening of the skin with local 
increase in temperature. 

If the irritation is mild, the great increase in the flow of blood 
through the part, other things being equal, will tend to eliminate 
the irritating chemical or other agent, thus fulfilling the biological 
function of the response and stopping the pathological process. 
Hyperemia favors physiological oxidation and the normal metabo- 
lism of tissue per unit of time. The increased volume of blood also 
brings a greater amount of oxygen in contact with the tissue at this 
stage, a reaction that would favor, not only the washing away of the 
injurious substances, but in some cases its oxidation and destruction. 
The physiological correlations induced by anemia and hyperemia 
are very important in this connection, topics that have been recently 
clearly and elaborately presented by Guthrie 1 in his book, Blood 
Vessel Surgery. 

The second stage of irritation is characterized by swelling, edema, 
blood stasis, and a great gathering of the migratory and phagocytic 
cells. This is associated with more or less acute pain and sensitive- 
ness of the involved local area. Briefly stated, the successive changes 
are: the gathering of white blood corpuscles along the walls of the 
dilated blood-vessels, soon followed by ameboid migration of these 
cells through the vascular endothelium and through the connective 
tissue and lymph spaces. It is apparent that the resistance of the 
endothelial tissue is reduced and that the ameboid response of the 
white blood cells and lymphocytes is increased. This stage is accom- 
1 Guthrie, C. C: Blood Vessel Surgery, p. 132. New York, 1912. 



DETAILS OF PHARMACOLOGICAL ACTION 



271 



parried by or followed by a corresponding increase in the amount 
of the exudations so that the plasma passes through the vascular 
walls, greatly increasing the extra-vascular fluid and producing the 
swelling or turgor of the part. In many local irritations, this process 
may be so strongly accentuated as to produce accumulation of fluid 
under such tension as to lift the corneous layer, forming vesicles or 
blisters. The fluid of the vesicles may contain the irritant agent 




Fig. G4. — Gathering of white corpuscles in capillaries of an inflamed area. 1. Ad- 
hesion to capillary walls. 2. Migration through the wall. From Lavadowsky. 

in solution. In the later stages of the diffusion there is stasis of the 
red blood corpuscles with extravasation. The movements of the 
lymphocytes and of the various white corpuscles is undoubtedly a 
chemiotactic response. Not only do these cells gather in large num- 
bers in the inflamed tissues, but they may and often do actively 
multiply so that their numbers are enormously increased. 

When the action of the irritant is extraordinarily severe there 
follows death of the protoplasm of many of the cells and the phe- 
nomenon of suppuration with disintegration takes place. This latter 
type of response is characteristic of that called forth by certain 
infectious organisms. Here there may be an enormous increase in 
the number of phagocytic cells especially of the polymorphonuclear 
type. The irritants of the class therapeutically called pustulants pro- 
duce this type of inflammation. The pus discharged consists of the 
excessive accumulation of corpuscles together with the disintegrating 
product of the dying tissue cells. 



272 IRRITANTS OF THE EXTERNAL SKIN 

One can distinguish at least three stages in the process between 
the incipient irritative action and actual cell death. These stages may 
be, though they are not always, called forth by the continued action of 
a strongly toxic irritant. The action may be mild and reach only the 
first stage, as, for example, simple inflammation. If the action is more 
vigorous and rapid, then the inflammation is followed by or reaches 
the stage of vesication. In other words, the edema may reach a point 
where there is an accumulation of lymph, therefore vesicles. The 
irritants may finally lead to a fatal termination in the tissue of the 
local area, for example, in the case of excessive cell disintegration, 
i.e., pnstulation. In this final or fatal termination, of course the body 
has failed in the response which would ordinarily meet the injury 
of the irritant. 

Where degeneration is only partial and the injurious agent is 
removed, a definite recuperative process takes place. Or if, as in the 
case of certain bacterial infections, its further action is prevented or 
at least diminished by a process in which the agency is walled off 
by constructive growth changes about the area of the infected focus. 
These reconstructive changes belong to the provinces of pathology, and 
the reader is referred to the extensive literature of pathology and 
bacteriology for its further description. 

3. The irritant action of the volatile oils. — The most important 
of the volatile oils are oil of turpentine, oil of pine, oil of juniper, 
Canada balsam, and myrrh. Several other substances, the most im- 
portant of which is chloroform, have similar action and physiologically 
could be classed in this group, though chemically they are very dif- 
ferent in character. These oils readily penetrate the skin and are 
irritants of varying degrees of toxicity to the underlying tissue. 
They act comparatively slowly and are milder in effect than are 
some of the other irritants, for example, cantharidin. 

4. The toxic gluocosides of the mustard series. — Oil of mustard 
is a highly irritant material which also readily penetrates the skin. 
It is derived from different species of Sin apis, the most com- 
mon being black mustard, or Sinapis nigra, and the white mustard, 
or Sinapis alba. The irritant oil is present in the seeds of the plant 
as a chemically inert glucoside. But the seeds contain a ferment 
which, upon being moistened with water, sets up a fermentive process 
in the glucoside whereby the actively irritant mustard oil is set free. 
The reaction proceeds according to the formula given on page 2. 
This reaction is utilized in the mustard plaster used for medicinal 
irritation. Ground mustard seed is spread out in a thin layer 



IRRITANTS OF THE CANTHARIDIN TYPE 273 

which, when moistened, slowly undergoes fermentation. When a 
mustard plaster is applied to the skin it is at first non-irritant, but 
as the mustard oil is slowly set free, it reacts on the body to produce 
inflammation. The longer the material is in contact with the skin, 
the more intense the inflammatory process, largely because of the 
accumulating quantity of mustard oil. An active clinical mustard 
plaster will produce redness and mild inflammation in fifteen minutes, 
and vesication in thirty to forty minutes in a sensitive skin. 

5. Irritants of the cantharidin type. — The highly irritant can- 
tharidin is soluble in oils and alcohol, but is only slightly water 
soluble though its salts easily pass into solution. 

It produces the most violent irritative changes in the tissues of 
any of the irritants thus far considered. It readily penetrates the 
skin and sets up local inflammation which produces the vesication. 
As small a quantity as 0.1 milligram is adequate to produce this 
effect on the human skin. 

The salts of cantharidin very readily pass into the general cir- 
culation and lead to vigorous inflammation in other parts of the 
body, particularly in the kidney, the bladder, and the uro- genital 
passages. The kidney is especially responsive to cantharidin, and 
nephritis is a common aftermath of the use of this drug. The 
glomeruli are the first to respond to its action, though changes take 
place over the entire nephridium. Cantharidin, taken by the mouth, 
is quickly absorbed. It has enjoyed a questionable reputation as an 
aphrodisiac, and too common poisoning occurs from its misuse for 
this purpose. Its application to the skin as an irritant has to be 
guarded in practice, lest sufficient of the poison be absorbed to pro- 
duce acute nephritis and other toxic reactions. 

The active principle of the American poison oak, or poison ivy, 
toxicodendrol, is even more highly irritant than cantharidin. In this 
case as little as 0.0001 of a milligram is sufficient to produce vesication 
of the skin. This plant is widely distributed and acute intoxication 
from it is only too common. In more susceptible individuals toxico- 
dendrol poisoning becomes quite a serious menace to general health. 
This irritant is soluble in alkalies and in alcohol, but is precipitated 
by lead acetate. After being exposed to its action, the prophylactic 
treatment should be to bathe the exposed part in alcohol in order to 
dissolve the adherent toxicodendrol and follow by an alcoholic solution 
of lead acetate or other precipitant to remove the poison before its 
action has proceeded far. 



CHAPTER XXXV. 

THE VEGETABLE CATHARTICS. IRRITANTS 
AFFECTING THE ALIMENTARY CANAL. 



Introduction. 

The substances of the vegetable cathartic group, like the skin 
irritants, are numerous. A large number of these substances are 
glucosid.es which, when the carbohydrate is split off, leave a highly 
irritant residue. They are usually divided into three great groups : 
1. The resinous glucosides, represented by the jalap group; 2. Vege- 
table cathartics of the anthracene group ; 3. Neutral oils which, upon 
digestion, set free an irritant fraction. 

The important representatives of the jalap group are: Jalap, 
Colocynthin, Podophyllum, Elaterium. The resin from jalap contains 
the irritant glucoside, convolvulin. Colocynthin contains in its fruit 
the glucoside, colocynthin. Podophyllin is a glucoside which has 
been isolated from the may-apple root. Elaterium is a neutral sub- 
stance, the most toxic member of the series. It is derived from the 
fruit of the Ecballium elaterium, or squirting cucumber. 

Typical members of the anthracene group are, aloes, senna, and 
rhubarb. These plants yield irritant substances of which the anthra- 
cene nucleus forms the base. 

The cathartic oils are two, namely, croton oil, which, upon diges- 
tion, sets free the highly irritant croton-olic acid, and castor oil, 
which splits off risinolic acid. These cleavages take place during 
the digestion of the oil. 

II. 

Outline of Pharmacological Action. 

1. The acceleration of the peristaltic contractions, both of the 
small and large intestines. 

2. Stimulation of the secretion of fluid by the mucous lining and 
by the glands of the alimentary tract. 

3. The production of local inflammation, which may become 
drastic when the drugs are used in more concentrated form. 

274 



THE XATURE OF THE ACTION OF VEGETABLE PURGATIVES 275 

III. 

Details of Pharmacological Action. 

i. The nature of the reaction by which the vegetable purgatives 
produce irritation and catharsis in the alimentary canal. — The 
recognition of the fact of the irritative action of the group called 
vegetable purgatives gives us a key for the explanation of their 
purgative action. The different members of this group induce varying 
degrees of irritation, and in different portions of the mucous mem- 
brane of the canal. As a result of this irritation there is disturbance, 
not only in the local area of the mucosa in contact with the drug, but, 
through the complicated nervous relations, marked changes in the 
reaction of the nerves controlling alimentary motor behavior and 
secretory processes. For the explanation, therefore, of the complex 
of catharsis induced by this series, one must hold in mind the entire 
physiological mechanism involved. This mechanism is described later 
in connection with the topic Saline Cathartics. At that point some 
emphasis is laid on the fact that the physiological movements of the 
stomach and of the intestinal tract are peristaltic in nature. Also 
that the large intestine is less vigorously active than the small 
intestine. 

Different physiologists, notably Langley, have laid emphasis on the 
presence and function of the local nervous mechanism, the enteric 
nervous system. While, the question has not been settled beyond 
doubt, the present indications are that the muscular walls of the 
alimentary tract execute their peristaltic actions under the influence 
and control of the peripheral nervous mechanism. At the same time 
the connections with the central nervous system supply the tract with 
general controlling nerve complexes, both motor and sensory. 

The various diverticula of the mucosa, which have become differ- 
entiated into the glands of the alimentary canal, are also brought 
into coordination with the muscular elements of the canal through 
regulating nervous mechanisms. With these anatomical and physio- 
logical relations in mind, we may venture to discuss the action of 
the drugs acting through irritation of the mucosa under the follow- 
ing points: 

2. Irritant action at the point of contact. — There is a great 
variation in the intensity of the reactions of the alimentary canal to 
different members of the vegetable cathartic group. This is partly 
due to the nature and time of contact as between the drug and the 
mucosa, and in part due to the toxic character of the drug. From 



276 THE VEGETABLE CATHARTICS 

the interaction of these two factors one may explain many of the 
physiological phenomena produced by members of this series. In 
making a comparison of the reactions one must constantly keep in 
mind that he is dealing with a water moist mucosa, a membrane that 
is very sensitive to contact environment, and a surface in which the 
time of contact with the cathartic drug is under the influence of 
the peristaltic contractions. In the very nature of the case only the 
early stages of the typical inflammatory processes are ordinarily 
induced. Emphasis has already been given to the fact that the 
initial irritative process is stimulative to the sensory nerve endings 
of the mucosa. The reaction to stimulation in the alimentary mucosa 
is a reflex change in motor activity, typically the induction of a 
strong increase in peristalsis. Hence, before an extreme inflammation 
is induced the increased motility will have driven the irritative agent 
forward, i.e., away from the point of contact before additional ab- 
sorption and further irritation has time to occur. This is particularly 
true of the small intestine. The large intestine, which under ordinary 
circumstances is stimulated to more vigorous persistalsis and final 
emptying by reflexes occurring at the bend in the rectum, is in many 
instances caught up in this general local irritative reaction. Not all 
members of the series produce equally intense reactions at different 
lengths of the alimentary tract, and the less irritative members, as a 
rule, react less vigorously on the large intestine. 

However, accelerated peristalsis will not account for all the phe- 
nomena observed. Many cathartics produce a great increase in 
the volume of the intestinal fluids, an effect which has been tested 
out experimentally on the isolated loops of the intestine. The in- 
creased fluid, under usual conditions, is not a transudate, since it 
is not characterized by the presence of albumin. On the other 
hand, it is held to be a secretion because the fluid contains digestive 
ferments. 

The vegetable purgatives, therefore, in the milder reactions pro- 
duce their local cathartic effect by three processes: (1) Increased 
secretion at the point of contact due to the mild local inflammation. 
(2) Stimulation to increased peristalsis, through local reflex mechan- 
isms, as well as through general nervous reflexes. And (3) reflex 
stimulation to secretion through the nervous control of the larger 
glands connected with the alimentary tract. 

The more irritant purgatives are extremely toxic; for example, 
elaterium. A very small quantity of this drug induces a violent in- 
flammation of the intestinal mucosa, which is shown by congestion 



PURGATIVE ACTION OF THE ANTHRACENE GROUP 277 

and destruction of the mucous membrane. Such a process leads to the 
more violent reflexes through the central nervous system, which at 
first are characterized by increased secretory and circulatory changes. 
When the contact is prolonged the systemic reactions may become so 
profound as to border on collapse. 

The cholagogue action of many of these drugs is explained by the 
calling forth of vigorous nerve reflexes, which produce contractions 
of the gall bladder, rather than by any particular influence they may 
have on the secretion of bile itself. 

3. Irritant action of the vegetable cathartics after absorption. — 
The majority of the vegetable cathartics are relatively insoluble; in 
fact, quite insoluble in the acid gastric juice. Their solubility is 
promoted by the alkaline secretions, which they meet in the duodenum. 
They are, therefore, absorbed slowly and reach the circulation in 
highly diluted form. That they are toxic after absorption, however,, 
is proven by the fact that they tend to induce inflammation in the 
kidney and in the uro-genital system. Even the mild aloes is some- 
times followed by renal ulceration. The more vigorous members are- 
prone to produce inflammation, not only of the kidney, but of other 
organs of the body not so intimately related to the elimination of the 
drugs from the system. It is for this reason that the large majority 
of the vegetable purgatives are contraindicated under certain con- 
ditions, as in the case of gastric and intestinal inflammation, nephritis, 
etc. 

4. Purgative action of the anthracene group. — The chief and 
best known members of this group of vegetable purgatives are senna, 
rhubarb, cascara, frangula, and aloes. Belonging to the same group 
in general chemical relation is the mild purgative phthaleins, es- 
pecially in favor since the work of Abel and Rowntree. 1 These 
authors studied the cathartic action of a number of phthaleins, show- 
ing that phenolphthalein, and more particularly phenoltetrachlor- 
phthalein, are mild and relatively non-irritant cathartics after hypo- 
dermic injection. 

The materials obtained from the anthracene group of vegetable 
purgatives have not been purified and isolated. They are used in the 
form of infusions, extracts, and syrups, made from preparations of 
the leaves and other parts of the plant. The group owes its purga- 

1 Abel, John J., and Rowntree, L. G. : " On the Pharmacological Action of 
Some Phthaleins and their Derivatives, with Especial Reference to their Be- 
havior as Purgatives. I.," Journal of Pharmacology and Experimental Thera- 
peutics, Vol. I., p. 231, 1909. 



CH CH 

S\ /\ 

HC C C 

i ii ii 


CH 
CH 


1 II II 
HC C C 

\/ \/ 
CH CH 


! CH 

Yh 



278 THE VEGETABLE CATHARTICS 

tive action to the substances which are apparently derivatives of the 
irritant anthracene nucleus : 



CmHk 



Attempts to isolate pure principles have proven only partially 
successful. As a group, the preparations are absorbed with difficulty, 
but when mixed with certain alkalies, for example, bile, they are 
more efficient. They act, therefore, largely on the intestine, chiefly 
the large intestine, where they are liable to produce considerable 
pain and tenesmus. 

a. Senna. — Preparations of senna are derived from the leaves of 
different species of cassia. Two cc, a half-gram, of the fluid extract 
or the equivalent dose of the syrup, the confection, or syrup of 
sarsaparilla, is usually adequate to produce cathartic action after 
six or eight hours. 

b. Rhubarb. — The preparations of rhubarb are derived from the 
root of Rheum officinale. The usual dose is 1 cc. of the fluid extract or 
four times as much of the tincture. Preparations of rhubarb were 
thought to be especially active in promoting the secretion of bile. 
This, however, is open to question. The facts are that the outpour 
of bile aids in the solution of rhubarb and facilitates its action by 
putting it into more intimate contact with the mucqus membrane of 
the intestinal tract. The presence of a certain amount of tannic 
acid gives to rhubarb an astringency which is antagonistic to its irri- 
tant action. 

c. Cascara is derived from the bark of Rhamnus purshiana. The 
action of the different preparations of this cathartic are mild and 
somewhat persistent. Cascara is unusually bitter, a property which 
is counteracted in practical uses by adding magnesium, licorice or 
some flavoring substance. 

d. Frangula is derived from the laxative bark of the alder-buck- 
thorn, Rhamnus frangula. 

e. Aloes is a somewhat more vigorous purgative derived from the 
juices of different species of aloe. It is given in doses of from three 
to five grains, and is characterized by the rather vigorous griping 
contractions which it induces in the large intestine and in the rectum. 



PURGATIVE ACTION OF THE JALAP GROUP 279 

It enters into a large number of the compound purgative mixtures of 
vegetable origin. 

/. Phenolphtluilein. — In recent years it has been shown that the 
different phthaleins have a mild laxative action on the alimentary 
tract. For example. 



Phenolphthalein, CaH^o'cjIl (OH) 



produces this effect in doses of .1 to .15 grms. The phthaleins are 
not very soluble. Abel and Rowntree especially investigated deriva- 
tives of phthalein, in particular phenoltetrachlorphthalein, which 
they consider favorable for human use as a hypodermic laxative. 
The most favorable members of the vegetable laxative series do not 
lend themselves to hypodermic injection, because of the local irritant 
action and inflammation which they induce. The phthalein com- 
pounds are particularly free from this action, inducing their favor- 
able reaction in the body through a stimulative rather than a strictly 
irritative process. Phenoltetrachlorphthalein is comparatively in- 
soluble in water, but is readily soluble in neutral oils. The authorities 
quoted used olive oil at a temperature of 210° C. in making their 
solutions. They gave hypodermic doses of .4 of a gram in 20 cc. of 
the oil. Catharsis did not occur until twenty hours or more, and 
continued in mild form for five or six days after administration. 

The phthaleins are soluble in the alkaline bile and are excreted 
from the liver through the bile. Ina" normal " case this brings the 
phthaleins into contact with the intestinal mucosa. In the mildly 
alkaline content of the large intestine some reabsorption takes place 
and later re-excretion through the liver, which, according to Abel and 
Rowntree, is a specific excretory organ for these compounds. It is 
probable that the cycle of excretion and absorption is the reason for 
the prolonged laxative action of the members of the phthalein group. 
Excretion takes place with the feces and, therefore, final elimination 
is assured. 

5. Purgative action of the members of the jalap group. — The 
representative members of this series are jalap, colocynthin. podo- 
phyllum and elaterium. The activity of this group is primarily due to 
the presence of irritant resins and glucosides. Here too the active 
principles have been only partially isolated. In comparison with 
the anthracene series this group is particularly irritant and toxic. 
One might raise a question as to the classification of the former group 
with the irritants, but not so in this group. Of all the members the 



280 THE VEGETABLE CATHARTICS 

most toxic is the squirting cucumber, Ecballium elaterium, which 
yields the active substance, elaterium. 

a. Resin of jalap. — .1 to .2 gram of jalap induce defecation in 
from two to three hours. Larger doses are highly irritant to the 
stomach and to the intestine. Jalap induces a marked secretion of 
fluid into the canal, which leads to the production of rice-water stools. 
The gastric irritation produces nausea and sometimes vomiting. 

o. Colocynth,. — The extract of colocynth is a purgative in doses of 
.03 to .05 gram. Its action is accompanied by intense griping, and 
in larger doses with bloody effusions. Brieger found that a small 
quantity of colocynth induced hyperemia and increased peristalsis 
in the isolated intestinal loop. The bloody effusions occasionally 
noted are due to acute inflammatory processes in the mucosa, which 
extend to the disintegrative stage and which involve the capillaries. 

c. Podophyllin. — In doses of from A to .6 gram podophyllin 
induces purgation in from six to ten hours. In doses of from 1.5 to 2 
grams there is nausea with mental depression, pain, and colic. The 
irritant action is prolonged with this resin, but it is somewhat re- 
duced or counteracted by hyoscin. 

d. Elaterium. — This is given in doses of from 1 to 3 milligrams, 
which induce purgation in two hours. This is the most drastic of all 
these purgatives. Stronger doses not only produce intense pain, but 
lead to severe inflammation, mucosal desquamation, and even collapse. 

6. The specific action of the neutral oil series. — The purgative 
oils of this series are castor oil and croton oil. Castor oil is an oil 
obtained from the seeds of the castor bean, Ricinus communis, by 
compression. The oil itself is not irritant, but when digested the 
ricinoleic acid is strongly irritant. Croton oil is obtained from the 
croton bean, Crotontiglium. Its methyl-crotonolic acid when set free 
is peculiarly toxic and irritant. The presence of minute traces of 
methyl-crotonolic acid in the usual commercial grade of this oil ac- 
counts for its irritant action on the skin and mucous membrane before 
its digestion takes place. 

a. Castor oil. — Doses as large as one-half to two ounces of castor oil 
are used to produce catharsis. This bland oil passes the gastric cavity 
with little change. It is true, it sometimes induces nausea and vomit- 
ing, but not from the specific action of the oil other than its disagree- 
able taste, especially when not perfectly fresh. In the intestines, how- 
ever, fatty digestion takes place, setting free the irritant ricinoleic acid. 
This induces a mild inflammation, which, in this particular instance, 
does not pass much beyond the limit of a general effusion. The 



ACTION OF CROTON OIL 281 

effect is vigorous enough, however, to produce variation of the peri- 
staltic movements with some reflex stimulation of the secretive mechan- 
ism, a result comparable to the mild resinous purgatives. Ricinoleic 
acid is generally regarded as only slightly more irritative and stimu- 
lative to the alimentary tract than the acids from the ordinary neutral 
oils ; for example, oleic acid. 

From this classification it is plain that castor oil has considerable 
value as a nutritive oil, as has the mild olive oil. In certain parts of 
the Orient, — for example, China, — castor oil is a general article of 
food. 

b. C rot on oil. — Upon intestinal digestion croton oil yields the 
highly irritant and toxic crotonoleic acid. A dose of croton oil is given 
by Hatcher and Sollmann as from 0.01 to 0.15 cc. (1-6 to 2 drops). 
There is usually enough free acid in the preparation to produce local 
irritation of the external skin ; therefore, to readily produce this change 
in the mouth and stomach. But when the lipases of the intestinal 
tract are met, additional neutral oil is dissociated and a more pro- 
nounced irritant action ensues. It is said that a single drop of the 
oil is sufficient to produce stools in from one to two hours, and the 
inflammatory action with its associated reflexes continues until as 
many as ten or fifteen stools result. In the case of croton oil the 
primary action is that of irritation and inflammation. A process that 
is most vigorous in the duodenal and lower intestinal mucosa. It is 
from such violent irritants as methyl-crotonoleic acid that most ex- 
tensive lesion of the canal becomes possible. As little as twenty drops 
is recorded as having produced death. 



CHAPTER XXXVI. 

COUNTER IRRITANTS AND THE PHENOMENON OF 
COUNTER IRRITATION. 

All agencies that induce local irritations have, beside a specific 
effect in the local region, reactions, which affect the coordinative 
mechanisms of the body. Such effects have long been known in 
practical medicine, and belong to the category of referred pain, counter 
irritations, etc. 

i. The theory of counter irritation. — The fundamental effect is 
that observed clinically when an inflammatory process of a given 
portion of the body, the skin, for example, induces favorable changes 
in diseased conditions of other and distant organs, in this illustration 
deep-seated organs, as the stomach, the lungs, etc. This knowledge 
has been, and to a considerable extent still is, largely empirical. 
Brunton x has summarized the facts showing the relation between 
specific local areas of the skin and particular visceral organs. One 
of his diagrams we use in Figure 65. The most satisfactory scientific 
explanation of these remote effects, an explanation that has received 
quite general acceptance, has been formulated by Head. 2 Head 
observed that the pain and areas of tenderness in deep-seated organs 
during visceral disease were associated with areas of tenderness in 
the local areas of the skin of the patient. In short, the skin tender- 
ness is an associated condition developed in connection with the 
diseased condition in the deeper organs. Briefly stated, his view is 
based on the segmental conception of the structure of the nervous 
system, viz., that the innervation of the different portions of the 
body is by nerves derived from segments of the brain and spinal 
cord. These nerves of each segment are subdivided into somatic and 
splanchnic branches. The somatic branches are superficial in their 
distribution, including the skin, muscles, etc., and the splanchnic are 
deep, including the various visceral organs. Both the sensory and 
the motor fibers of each typical segment participate in the superficial 
and deep distribution. 

1 Brunton, T. L. : Lectures on the Action of Medicines. New York, 1899. 

2 Head, Henry: Brain, Vol. XVI., p. 1, 1893. 

282 






THE THEORY OF COUNTER IRRITATION 



283 



From the standpoint of counter irritation, the sensory nerves, the 
vasomotors, and probably the trophic nerves are of greatest impor- 
tance. That these groups of nerves are in close physiological, as well 
as anatomical, relation to each other as regards their centers in the 
spinal cord, can no longer be doubted, although the explanation of 
particular cases has not always been perfectly free of question. In 



Laryngitis tit. 



Pericar- 
ditis 



Gastritis 




Fig. 65. — Cutaneous areas which are ordinarily used in the application of counter- 
irritants for the relief of inflammation of the deeper organs in the diseases indicated. 
From Brunton. 



Head's words, " Thus to sum up, I think we may conclude that the 
central connections of the pain fibers from the skin and viscera are 
closely connected with one another. The central connections of the 
nerves for heat and cold, and for trophic disturbances in the skin, 
must also be in somewhat close association, though probably not 
actually connected." According to the views of Head, and later 
of McKenzie, it is assumed that the cutaneous sensory nerves from 
a given segment, for example, from a typical skin area of the trunk 
region, are in close and intimate relation with the visceral nerves of 
that particular segment of the spinal cord, or, according to McKenzie, 
with closely adjacent segments. This relation is so intimate on the 



284 COUNTER IRRITANTS 

sensory side of the nervous complex that a sensory stimulation oc- 
curring in the viscus may be referred to an origin in the more highly 
innervated skin, or under certain circumstances vice versa. This is 
presumably because the collateral connections, either in the basal 
segment of the cord or at some higher level in the path, permit the 
nervous overflow of afferent impulse into a common area of perceiving 
cortex. Ordinary tactile, and for the most part temperature sensa- 
tions are absent from visceral organs. The visceral sensory or affer- 
ent impulses are chiefly those of the reflex and automatic type not 
associated with very definite states of consciousness. Visceral pain 
and the sensations of " fullness " characteristic of hollow organs 
(Hertz) are the chief visceral sensations. Perhaps appetite and 
hunger should be considered of this class. These sensations are 
not very definitely localized. It is for this reason that the symp- 
toms noted in connection with excessive visceral stimulation, or 
sensitiveness from inflammation, are readily interpreted as an ap- 
parently greater irritability of the corresponding cutaneous sensory 
areas associated with the same spinal segment. There is in fact an 
increase in the sensitiveness of the segmental centers, such that the 
usual cutaneous stimulus produces a greater response. Centrally the 
effect is the same as if the increase had come either from a stronger 
peripheral stimulus, or from a more sensitive cutaneous end organ. 

Cutaneous stimulation that results in vascular reflex dilations 
in the skin area will at the same time produce a similar degree of 
vascular change in the deep-seated organ whose coordinating vascular 
nerves are through the same spinal segment. That is, a light cutaneous 
stimulus, which is accompanied by a reflexly increased vasomotor 
tone, i.e., vasoconstriction, will normally produce definite vasoconstric- 
tions, not only in the skin segment, in which the stimulus arises, but 
in the corresponding visceral region. In certain particular regions 
there is a primary antagonistic reaction in these correlated areas. 

It is observed that a pathological condition, for example an in- 
flammation, of a deep-seated organ may have its blood-supply pro- 
foundly influenced by stimulative, i.e., irritative, processes occurring 
in the corresponding skin segment, and vice versa. Vasodilations 
favor and constrictions retard the reparative cycle. This is the un- 
derlying physiological principle justifying the application of skin 
irritants, such as artificial heat, poultices, mustard plasters, fly blisters, 
etc., for purposes of counter irritation. By the above hypothesis, 
the whole explanation of the phenomenon of counter irritation rests 
upon the anatomical and physiological close association in the cord 



THE THEORY OF COUNTER IRRITATION 285 

and brain-stem of the mechanisms of the automatic and autonomic 
reflexes coordinating the great nutritive areas of the body. In prac- 
tical therapeutics the whole process falls back upon the relation of 
the condition of anemia and hyperemia to metabolism, healing, etc., 
as suggested above. 

A question might be raised here in the application of Head's 
explanation in the consideration of the disease known as Herpes 
zoster. The cause of herpes, according to Head, has been ascribed 
to disease of the posterior root ganglia, i.e., inflammation and 
hypersensitiveness of the sensory paths. There is, therefore, an inter- 
ference with the reflexes arising from stimuli occurring in the areas 
to which the sensory fibers are distributed. It is definitely stated by 
Head 1 : " There is no evidence that deep organs receiving their 
visceral supply from affected roots become affected during the out. 
burst of zoster." On the theory of associated innervation it would 
seem that we have a right to expect an inflammatory process, not only 
in the skin, which does occur, but also in the corresponding visceral 
segment, which apparently does not occur in zoster. If the deep 
visceral reflex were looked for in a region containing antagonistic 
vascular associations, then the visceral region would display not 
hyperemia, but anemia, and Head's result would be expected. How- 
ever, the inflammation of the ganglion interrupts the normal reflexes, 
therefore the closely coordinating center or centers in the cord will 
not receive the extensive stimulation which characterizes the usual 
and uncomplicated process of counter irritation. 

Irritant drugs or other agents produce the changes associated in 
counter irritation when acting through some considerable period of 
time, and with a certain favorable degree of intensity. This is one 
of the distinguishing factors between a stimulus and a so-called 
" irritation." If the irritating agent be a drug, for example, a lini- 
ment, it produces its effect by direct contact with and absorption into 
the living tissue. Under ordinary conditions this contact is only 
eliminated by the slower vascular reactions of the body, which remove 
or isolate the agent, a process illustrated by the reactions to bacteria 
and to toxins. 

A large portion of the good influences of a counter irritant un- 
doubtedly comes from the reflex influences on the circulation. This 
is shown by the fact that a cutaneous irritant produces a rise of 
general blood-pressure, a rise that is attributed not to the changes in 
the blood-vessels of the skin areas alone, but to general vascular con- 
1 Head, Henry: Albutt's System of Medicine, Vol. VIII., p. 630. 



286 



COUNTER IRRITANTS 



strictions through the splanchnic region. It seems to follow that 
much of the favorable reaction in the class known as counter irri- 
tant processes is bound up in the better metabolic conditions induced 
by the correlations of the vascular mechanism. 

2. Conditions which suppress counter irritation. — In the preced- 
ing paragraphs emphasis has been placed on the segmental relations 




Fig. 66. — Front view, and Fig. 67. — Back view. — Areas of cutaneous innervation 
from different segments of the cord. These areas are found to closely correspond to 
areas of inflammation observed by Head in his study of the disease Herpes zoster. 
From Head. 



of the nervous mechanisms as between the skin and the deeper organs, 
i.e., between the somatic and splanchnic divisions of nervous con- 
trol. It might be expected from this that any agent which will 
break the reflex path will tend to prevent the counter irritant 
changes. This has been found to be the case. A counter irritation, 
in fact a direct irritation, is relieved from much of its effects if the 
irritant is applied after an anesthetic for the area. In other words, 
if analgesia be produced in an area and then an irritant applied, 
the usual end results are largely prevented. In the same way, if a 
styptic is applied, so that the reflex blood vascular dilation is pre- 
vented, the inflammatory process is diminished, at least delayed. 



COUNTER IRRITANT AGENTS 287 

3. Factors in the practical application of counter irritants. — 
Most text-books on therapeutics give directions for the practical use 
of counter irritants, and include precautions to be observed in the 
adaptation to different physiological conditions that may be met where 
such agencies are called for. A reference to Figures 66 and 67 will 
at once show the segmental nerve distributions to the skin, which 
must be kept in mind in the practical use of counter irritants for the 
relief of congestion in the thoracic or visceral organs. 

4. List of counter irritant agents. — From the discussion of the 
nature of counter irritants it is observed that the number of drugs or 
other agents which will induce the pharmacological change is large. 
Some of these agents are mechanical, but most of them are chemical. 

Of the mechanical agents heat and cold lead the list. Both heat 
and cold are capable of application in such a way as to cover a wide 
range of intensity of action, and the facilities by which they may be 
applied to different parts of the body in these days of special mechan- 
isms, particularly of the electrical class, make them the most valuable 
of counter irritants. Cold controlled by the ice bag is valuable in 
two great ways : first, in controlling the vascular reactions, and 
second, in depressing metabolism not only of the tissue, which is being 
acted on by the direct irritant, but, in those cases where there is a 
bacterial invasion, control of the injurious bacteria themselves. 

Drugs which produce irritation of any kind may be relied upon 
in the same moment to produce counter irritation, especially when 
the primary irritant is applied to the skin. Irritant processes in the 
visceral mucosa are not to be neglected in this regard, since they 
may lead to irritant processes in the somatic region. 

The counter irritant drugs range in intensity of action all the 
way from the mild processes induced by the saline baths to the 
violent referred reactions set up by the more vigorous caustics. 
For the discussion of the action of individual members of this series, 
the reader is referred to members of the group, Skin Irritants, which 
are the drugs most in favor for the production of counter irritation. 



PART II 

INORGANIC DRUGS. 

K. Drugs Characterized to Greater or Less Extent by Salt Action. 

CHAPTER XXXVII. 

UNDERLYING PRINCIPLES OF SALT ACTION. 



General Considerations of the Physical and Chemical Character- 
istics of Salts in Solution. 

i. Crystalloids and Colloids. — Physiology has, to a great extent, 
familiarized us with the different behaviors of the great variety of 
substances which we introduce into the body as foods. We have 
learned that the different classes of foodstuffs are in reality represent- 
atives of the great classes of chemicals. The proteins, fats, carbohy- 
drates, etc., i.e., the organic foodstuffs, undergo elaborate processes 
of digestion before they can enter the tissues, while the substances 
of simpler composition, such as the salts of sodium, potassium, calcium, 
etc., pass from the alimentary canal into the tissues and reach the 
circulation with little or no change. In a word, the inorganic salts, 
as soon as they enter the state of solution, can by relatively simple 
processes pass through the lining tissues of the alimentary tract, as 
well as through the walls of the blood-vessels, and thus quickly dis- 
tribute themselves throughout the body. 

When these great classes of materials are examined more critically 
the striking characteristic is the fact that the salts pass readily into 
solution, while the organic substances are dissolved with difficulty or, 
it may be, not at all. These are differences which rest on a physical 
basis and are expressed by the terms which designate the classes, 
namely, crystalloids and colloids, a classification which was made by 
Graham a half century ago (1861). Graham called the bodies which 
passed through a membrane crystalloids because they were found to 
be such substances as the salts of sodium, potassium, lithium, etc.j 
which exist in the crystalline form. Those substances which do not 
diffuse through a membrane were designated as colloids. 

288 



ELECTROLYTES 289 

2. Colloids. — This class is characterized by the relatively large 
size of the molecules, also by the fact that they behave in a charac- 
teristic way when in solution or suspension. The colloids are of 
special interest in pharmacology for the reason that they enter so 
largely into the composition of the tissues. They influence the be- 
havior of these tissues, not only by virtue of their chemical nature, 
but also on account of their purely physical characteristics. The 
presence of the colloid markedly influences the movements and 
relations of the molecules and ions of the salines, i.e., the crystal- 
loids. 

3. Crystalloids. — Crystalloids are distinguished from the colloids 
by the fact that they go into solution far more readily. They for 
the most part pass through animal membranes with comparative ease, 
and in a general way are far more labile than are the colloids. The 
size of the molecules in the crystalloids is relatively small, many times 
smaller on an average than in the colloids. 

4. Dissociation. — "When the molecules of a crystalloid pass into 
solution they undergo dissociation, whereby the atoms or groups 
of atoms are separated, carrying electric charges. For example, when 
sodium chloride is dissolved the molecules of the salt break down 
or dissociate into electrically charged ions. The sodium ion carries 
a positive charge, and is called the cation. The chlorine ion carries 
a negative charge, and is called the anion. This process of dissocia- 
tion, or ionization, occurs in practically all inorganic salts. Dissocia- 
tion, however, does not necessarily break the molecule into simple 
atoms electrically charged. Many of the anions and cations consist 
of groups of atoms as in sodium nitrate, NaN0 3 , which dissociates 

into positive sodium ions, Na, and negative nitrate ions, N0 3 . Sucli 

substances as caustic potash, KOH, dissociate into K and OH ions. 

+ 
the acids as hydrochloric acid, HC1, into H and CI ions. 

5. Electrolytes. — Solutions of crystalloids are conductors of elec- 
trical currents, hence called electrolytes. This is dependent upon the 
state of ionization; in fact, the conducting power of a given solution 
is proportional to the content of ions. The cations carry positive 
electricity, and migrate toward the negative pole when a current 
is flowing through the solution. The anions migrate in the opposite 
direction. The conducting power of a solution varies with the dif- 
ferent chemical substances in solution, depending not only upon 
the number of ions, but upon other diffusion constants. Certain ions, 



290 UNDERLYING PRINCIPLES OF SALT ACTION 

for example, migrate through a solution with much greater speed 
than others. 

6. Freezing point depression. — The factor of dissociation is 
shown by the influence which the molecules and ions have on the 
depression of the freezing point of a solution. In this instance both 
the molecules and the ions act as individual particles in influencing 
the freezing point. It is found by experiment that the freezing 
point depression is directly proportional to the sum of the molecules 
and ions in solution. "When this factor is measured in terms of known 
constants it is evident that the freezing point gives a direct measure 
of the dissociation percentage in any given solution. Sodium chloride, 
0.9 per cent., which is isotonic for animal tissue, is found to lower 
the freezing point by 0.56°C. (Hamburger), i.e., the pressure equiva- 
lent of 6.5 atmospheres. 

7. Osmotic pressure and osmosis. — When chemical substances 
go into aqueous solution there begins at once the process of distribu- 
tion of the molecules, also the ions if the chemical be dissociable, 
throughout the volume of the solvent. The particles of the salt dis- 
tribute themselves through the solvent according to certain laws. 
If a certain volume of gas be turned loose at the gas jet in a room, 
then the laws of gaseous diffusion come into play, and, other things 
being constant, the molecules of gas will distribute themselves equally 
throughout the space of the room. Just so is it with a salt dissolving 
in a beaker of water. The particles of the salt begin to diffuse 
from their initial location until equilibrium is established. It will 
then be found that the salt has distributed itself so that each cubic 
centimeter of the solvent contains the same quantity or number of 
molecules of the salt. When non-reacting salts are dropped into 
the solvent at the same time each salt dissolves and diffuses accord- 
ing to its own volume and properties. Each is independent of the 
other just as in the case of the diffusion of two or more gases in a 
mixture. 

In gases this phenomenon is explained by the fact that each 
molecule of gas is in free motion with reference to all other molecules 
in the mixture. Just so is it with the molecules of a salt. Each 
molecule and ion is in motion and the motion is not hindered by 
the solvent, hence the ultimate uniform distribution through the 
solution. 

8. Osmosis. — In animals and plants the tissues are separated from 
each other by surface membranes, though in many animal tissues this 
surface membrane is not well marked. Such membranes impede the 



OSMOSIS 291 

diffusion of dissolved molecules. Dead membranes prepared for ex- 
perimentation are found to differ sharply in character. Some will 
allow the free passage of water, but prevent the passage of dissolved 
substances. These are called non-permeable membranes. Others will 
allow the passage of certain molecules of dissolved substance and will 
hinder the passage of others. These are called semi-permeable mem- 
branes. If the molecules of the salt as well as the solvent pass freely 
through the membrane, then it is designated as a permeable mem- 
brane. 

Osmotic pressure is shown by instruments which permit the pas- 
sage of water but prevent the passage of salt molecules. In such an 
apparatus, where the membrane separates pure water from a solution 
of a salt in water it can be shown that the water will diffuse into the 
salt solution as against an ever increasing pressure. When such a 
diffusion has reached a state of equilibrium the pressure of the salt 
solution will have increased an amount which is in direct proportion 
to the increase in number of molecules and ions per unit volume. 
This passage of water through such a membrane is called osmosis. 
The pressure which it induces in an osmotic apparatus is called 
osmotic pressure. 

If the membrane is semi-permeable, then the relations are some- 
what different. In this case, if one places on one side of the mem- 
brane a mixture of salts in solution some of which can penetrate the 
membrane and some not, and on the opposite side of the mem- 
brane distilled water, then immediately water begins to pass through 
the membrane into the salt solution, while the permeable salts will 
begin to diffuse through the membrane into the distilled water. The 
non-permeable salts are, of course, retained on the original salt side. 
In this case the passage of the permeable salts by so much reduces 
the osmotic pressure of the salt solution. Since the rate of diffusion 
of the salts will vary in each individual case, the osmotic pressure 
will be represented by a certain curve, which at first rises, because of 
the more rapid diffusion of the water through the membrane, then 
more slowly falls as the diffusible salts pass through and distribute 
themselves throughout the liquid on the water side of the membrane. 
When equilibrium is established the osmotic pressure on the saline 
side of the membrane will be represented by the pressure of the non- 
diffusible salts only, the diffusible salt being equally distributed on 
both sides. 

In permeable membranes a transient osmotic pressure may mani- 
fest itself on one side of the membrane as compared with the other, 



292 UNDERLYING PRINCIPLES OF SALT ACTION 

because of the different rates of diffusion of the different components 
of the mixture. 

The reader will need to consult works on physical chemistry for 
the mechanism of this process. It is of interest to pharmacologists 
because osmotic pressures play such an important part in the behavior 
of living tissues in relation to numerous drugs as well as to salt 
solutions. 

The influence in the body of saline solutions exerted by virtue of 
their osmotic, electrolytic, and other physical factors is designated by 
the general term salt action. 

The protoplasm of the tissues in the animal body does not form 
quite the same type of surface membrane as is found in the dead 
osmotic membranes. Nor, in fact, do we find such typical membranes 
as are present often in the botanical tissues. However, osmosis and 
isotonicity are always operative factors in the animal body. The 
protoplasm contains colloidal material, and often this material is 
condensed into a relatively efficient surface membrane over the 
animal cell, as in the case of the red blood corpuscles. LWhen salt 
solutions come into contact with the tissues a process of diffusion 
as between the solution and the tissues immediately takes place. It 
will continue until a degree of equilibrium has been established./ 
Unprotected animal tissues will rapidly absorb distilled water by 
virtue of the osmotic pressure due to the protoplasmic saline content. 
In like manner they will lose water to solutions of greater concen- 
tration, as is shown when red blood corpuscles crenate in hypertonic 
salines. 

The colloids, as differentiated in the tissues, vary greatly in their 
permeability to different salines. Certain solutions, as ammonium 
chloride, penetrate practically all tissues with great facility, acting 
essentially as so much distilled water. Under its influence the blood 
corpuscles will swell to the point of bursting, and muscle and 
other tissues undergo a similar increase in volume. Other salts, as 
sodium chloride in the case of the red blood corpuscles, or the sulph- 
ates in the alimentary canal, do not readily pass through the surface 
of the tissues, and to that extent control the water content of the 
tissue. A solution of non-permeable salt will lose water to, draw 
water from, or maintain an equilibrium as regards the water content 
of a tissue, according as it is hypotonic, hypertonic, or isotonic with 
the tissue. 

It is obvious that salt action plays a very important part in 
maintaining a proper water content of the tissues of the body. 



GENERAL CONSIDERATIONS 293 

In other words, salt action is in a very large degree responsible for 
maintaining an efficient dilution of the chemical components of living 
substance, under which the protoplasm carries on with the greatest 
economy its reactions and its corresponding expenditure of energy. 



CHAPTER XXXVIII. 
WATER. 

The introduction of water into the body or the bringing of water 
into contact with any portion of the body which it wets leads im- 
mediately to disturbances of the osmotic balance of the tissues and 
parts. Of course the skin, which is oily, is relatively impermeable to 
water, though a certain amount of water is taken up by long contact 
with the corneous epithelium. The changes induced in the body by 
the action of water depend chiefly on three factors, namely, the 
volume of the water, the length of time during which it is kept in 
contact with a given tissue, and the osmotic permeability of the 
tissue. 

i. Action of distilled water on isolated tissues. — When isolated 
tissue, such as the gastrocnemius muscle or glandular tissue, is 
immersed in distilled water the cells of the tissue act like osmometers. 
They imbibe water. The water passes through the surface membrane 
into the protoplasm as into a colloidal solution. The percentage of 
water in the tissue, therefore, increases and a condition of hydric 
edema supervenes. This water-logging of the tissues interferes with 
the normal physiological reactions, and if carried too far it leads to 
degeneration, hence the destruction of the tissues. 

A rhythmically contracting strip of cardiac muscle when im- 
mersed in distilled water will continue its rhythm for some time, 
but the relaxation process is interfered with. The rhythm ultimately 
ceases, therefore, with the muscle in the systolic phase. Skeletal 
muscle is somewhat similarly influenced. These results are due not 
only to increase in water content, but to a loss of saline constituents, 
especially from the interstitial spaces of the muscle. 

It is not so easy to determine the exact changes in the func- 
tional activity of glandular tissues, but they too absorb water and 
swell. 

Certain living organisms like protozoa, embryos, such as those of 
the fish, for example, fundulus, and certain special modifications 
of tissue like the epithelium of the giUs of fishes, withstand the action 
of distilled water with a remarkable degree of resistance, provided 

294 



DRINKING WATER 295 

the water contains no toxic impurities to vary the normal resistance 
of these tissues. It is true that organisms often thrive better in 
waters derived from natural sources, such as springs and the like, 
but such waters contain one or more saline constituents, which are 
the favorable ingredients. 

2. Drinking water. — An individual takes large quantities of water 
as a part of his necessary daily food. This water is brought into 
contact for some time with the lining membrane of the stomach and 
intestine, through which it is ultimately absorbed. Water taken by 
the mouth, therefore, ultimately reaches the blood stream and is 
distributed throughout the body. Experimental physiology teaches 
us that very little water is absorbed from the stomach, but that ab- 
sorption from the intestine is free and rapid. Water enters the body 
so slowly by this channel that it is very gradually distributed, with 
the result that it never at any time very sharply raises the percentage 
of water content of the body fluids and tissues. For example, a glass 
of water, which contains 250 cc, will be absorbed within 20 to 30 
minutes. Since the proportion of blood is approximately one-thirteenth 
the body weight, the glass of water in a man weighing 130 pounds 
would be distributed in ten pounds of blood, i.e., about 5000 cc. 
Since this blood comes into contact with the tissues every 30 seconds, 
the further distribution of the water obviously would take place so 
rapidly that the water percentage of the tissues would never be 
increased from the operation more than a fraction of one per cent. 
Conditions of extreme thirst are usually associated with diminished 
water in the tissues, i.e., hypertonicity in the system. Under these 
conditions the absorption of as much as one or two liters of water 
would only increase the water content of the tissues by one to three 
per cent., assuming no elimination during the absorption. 

Whether or not the drinking of large quantities of water with our 
daily meals is injurious has recently been put to test by Dr. Hawk 
in the University of Illinois laboratories. It would seem that the 
taking of large quantities of water with meals, i.e., at the beginning 
or close of the meal, not with the mastication of the foods, is followed 
by relatively slight or insignificant influences on either the efficiency 
of the digestive processes or the utilization of the foods in tissue 
metabolism when tested against the usual and ordinary methods of 
taking drinking waters. 

3. Mineral waters. — Mineral waters should rather be regarded as 
solutions of certain salts. Therefore, the reactions of the body to 
these special waters can best be designated under the headings involv- 



296 WATER 

ing the particular salts contained in the particular waters. The 
reader is accordingly referred to those sections. 

4. The influence of water on metabolism and on the kidney. — 
There is one phase of the influence of water on metabolism that 
should not be lost sight of, namely, the fact that a relatively high 
water content of the tissues is associated with the period of greatest 
growth and physiological activity during the life cycle. This state- 
ment is particularly true with regard to the growth processes. The 
tissues of embryos and of the developing young always contain a 
relatively high percentage of water as compared with the same tissues 
of adults. As an example of this fact may be quoted the rate of repair 
in the epidermis of frogs kept at different isotonic levels as regards the 
salt content of their tissue fluids. Hypotonic frogs repair their tissues 
much more rapidly than hypertonic frogs. ■ 

A hydremic condition is favorable to a greater excretion of water 
by the kidney. Very excessive ingestion of water, therefore, is rather 
quickly adjusted by elimination through the excretory organs. In 
other words, pure water is a sharp and efficient diuretic. The large 
quantity of urine excreted under this condition eliminates not only 
water, but the water carries with it both salts and waste organic prod- 
ucts. These are present, however, in relatively less condensed form. 
Under extreme toxic conditions where the absorption of water from 
the alimentary tract is too slow for efficiency sterile distilled water 
may be injected directly into the veins, of course in moderate and 
guarded amounts and preferably in the form of isotonic physiological 
salines. 



CHAPTER XXXIX. 
ISOTONIC PHYSIOLOGICAL SOLUTIONS. 

Artificial physiological solutions have been in general use now since 
1869, when Nasse * gave us the basis for our physiological saline. 
Such solutions primarily attempt to maintain the physical factors 
of the blood serum and the body fluids. This is accomplished by a 
mixture of salts in such proportion as to be isotonic with blood serum. 
Of these solutions the ones in most common use are physiological 
saline, Ringer's solution, Locke's solution, and other similar solutions 
with minor variations made to improve the exact physiological balance 
of the constituents. Artificial physiological solutions are often of 
extreme practical value in supplying great loss of blood, or in other 
pathological conditions of one sort or another. They have been of in : 
estimable value in scientific research on living tissues. Physiology 
teaches us that many of the protoplasmic differentiations in the ani- 
mal body continue to live and exhibit normal reactions through re- 
markably long periods when they are bathed in these solutions. If 
the saline solutions are kept sterile and adequately aerated they are 
even quite adequate to the growth needs of isolated tissues for a 
limited time. 

i. Physiological saline. — That sodium chloride in 0.6 per cent, 
solution would maintain the striated muscle of a frog in a living active 
condition for a long period was first shown by Nasse. Similar 
experiments were applied to other organs and tissues of the body, 
the first being the cold-blooded heart. Out of this classical beginning 
has arisen all the present extensive use of artificial solutions for 
physiological, pathological, and practical medical purposes. 

Physiological saline is made up in adaptation to the blood and 
tissues of each animal according to the isotonicity of its serum. For 
mammals this isotonicity is represented by a 0.9 per cent, sodium 
chloride solution. Isolated tissues and organs of the cold-blooded ani- 
mals, and to an extensive degree of the warm-blooded animals also, 
remain active and living in physiological saline for several hours. 
However, physiological saline is not a chemically indifferent solution 

1 Nasse, 0.; Arch. f. d. ges. Physiologie, 1869, Vol. 2, p. 118. 

297 



298 ISOTONIC PHYSIOLOGICAL SOLUTIONS 

characterized by physical properties alone, as is too often taught. 
It fails to support continued tissue activity as would the serum of the 
animal. The solution is not toxic in the usual sense, but merely fails 
to supply certain needs of the living tissue. Under its influence iso- 
lated hearts at first contract strongly and with good rhythm, but later 
rapidly lose their amplitude of contraction, though rhythmicity may be 
retained for a longer time. Skeletal muscle rapidly diminishes in ir- 
ritability. Cushing has shown that the power of the nerves to trans- 
mit a stimulus to the muscle drops out even earlier than the irritability 
of the muscle to which the nerve may be attached. Such experiments 
strongly argue against the efficiency of the purely physical factors in 
all artificial physiological solutions. 

The matter may be looked at in another light. Isotonicity obtained 
by a single salt does not and cannot maintain a physical balance 
against a body fluid in which the osmotic pressure is due to a complex 
of salts. Living tissues lose to physiological salines certain necessary 
ions, and this in itself ultimately disturbs the physical balance in 
such a way as to change the physiological reactive property of 
the tissue. 

2. Perfusions of physiological salines. — Physiological saline is in 
practice introduced into the body by one of two methods, either by 
hypodermoclysis or by transfusion directly into a vein. In- the former 
case the saline enters the body relatively slowly, though large amounts 
may be introduced by the method. In the second case the saline 
enters the blood stream directly and is under the control of the 
manipulator. Sterile physiological saline may be transfused without 
danger for as much as 20 to 30 per cent, of the total normal blood of 
an animal, one to two liters in the case of man. It is evident 
that this gives a valuable agent for quickly returning the necessary 
volume of blood in cases of excessive loss from traumatism, etc. The 
amount of blood in a normal average adult is from six to eight liters, 
i.e., one-thirteenth of the body weight. The introduction of two addi- 
tional liters, even when one-third the normal blood is lost, will give 
a blood mixture that contains only approximately 30 per cent, physio- 
logical saline, and this percentage is very quickly lowered by inter- 
diffusions between the blood and the tissues of the body. Such a 
dilution of the blood is far less drastic in its effect on the tissues than 
is generally supposed, less, in fact, than in experiments on isolated 
organs immersed in a pure physiological saline. The isotonicity fac- 
tor throughout is maintained at a constant, the sodium chloride con- 
tent of the plasma is constant, while the other saline constituents 



RINGER'S SOLUTION 299 

of the plasma and tissues are lowered, yet not so violently disturbed 
and hence readily regain their balance. 

There are numerous experiments that indicate that the sodium 
chloride, as such, is mildly stimulative to protoplasmic activity. 
Granting this point, it follows that its addition as physiological 
saline to the extent of as much as 30 per cent, of the volume of the 
blood will slightly raise the irritability, i.e., the general activity of 
the tissues. This, of course, is favorable in the case of excessive 
shock, excessive bleeding, etc., where the clinical use of physiological 
saline or other normal physiological solution is called for. 

The introduction of relatively large volumes of physiological 
saline causes slight rise of blood-pressure purely because of the in- 
creased volume of blood. This factor is favorable to the eliminative 
processes, the chief of which is the excretion of fluid through the 
kidney. Physiological saline is a diuretic, therefore. In driving a 
large quantity of fluid through the kidney a considerable quantity of 
the saline constituents of the blood are carried along. The process 
also favors the elimination of organic waste products, such as urea, 
etc., and of toxins, drugs, etc., just as happens when there is an 
increase of the volume of blood by the absorption of drinking water. 

3. Ringer's solution and its modifications. — In the early eighties 
Ringer cleanly showed that physiological saline was inadequate be- 
cause it lacked certain necessary salts present in the serum, namely, 
potassium and calcium salts. From his work we have derived the 
numerous physiological solutions which bear his name. 

A wide variety of percentages of constituents in Ringer's solution 
has been used, especially in recent times. This is due to the attempt 
to maintain the actual saline balance which exists in the blood serum 
of the animals used in the experimentation, the different species vary- 
ing widely in this regard. Loeb 1 states : ' ' We have a point of at- 
tack for the investigation of the role of the salts in the fact that the 
cells of our body live longest in a liquid which contains the three 
salts, NaCl, KC1, and CaCl 2 in a definite proportion, namely, 100 
molecules NaCl, 2.2 molecules KC1, and 1.5 molecules of CaCL. This 
proportion is identical with the proportion in which these salts are 
contained in sea water; but the concentration of the three salts is 
not the same in both cases. It is about three times as high in the sea 
water as in our blood serum." In laboratory practice it is found that 
for cold-blooded vertebrate and for mammalian tissues the percentage 
of potassium and calcium is a little higher. The physiological bal- 
1 Loeb, Jacques: The Mechanistic Conception of Life, p. 169. 



300 ISOTONIC PHYSIOLOGICAL SOLUTIONS 

ance was determined for terrapin ventricular tissue by Greene x and 
is represented by the following solution: 

0.7 per cent, sodium chloride 
0.03 " " potassium chloride 
0.026" " calcium chloride. 

Certain laboratories slightly increase the amount of potassium 
chloride for use with mammalian tissue up to 0.042 per cent., and 
add a trace of alkaline sodium bicarbonate. The amount of calcium 
in the above mixture is based on quantitative analytical determinations 
in sheep serum (Howell) and terrapin serum (Greene). 

The Kinger's solution not only maintains total isotonicity as such, 
but it maintains an isotonicity of the three most important salines 
of the body fluid. In oxygenated Ringer's solution many of the body 
tissues behave remarkably like normal tissues. 

The inorganic salts in Ringer's solution are not supposed to 
furnish potential energy, still these salts are essential to the living 
activities of the body tissues. Quoting again from Loeb: " If we 
now raise the question as to why salts are necessary for the preserva- 
tion of the life of the cell, we can point to a number of cases in 
which this answer seems clear. Each cell may be considered a 
chemical factory, in which the work can only go on in the proper 
way if the diffusion of substances through the cell wall is restricted. 
This diffusion depends on the nature of the surface layer of the cell. 
Overton and others assume that this layer consists of a continuous 
membrane of fat or lipoids. This assumption is not compatible with 
two facts, namely, that water diffuses very rapidly into the cell, and 
second, that life depends upon an exchange of water-soluble and not of 
fat-soluble substances between the cells and the surrounding liquid." 

A definite nutritive substance was first added to the Ringer's salt 
solution by Locke. 

4. Locke's solution. — Locke added 0.1 per cent, of dextrose to 
Ringer's solution in the attempt to furnish the tissues with a definite 
oxidizable energy-giving substance. He found that the addition pro- 
longed the life of the tissues beyond that of strictly inorganic 
Ringer 's. 

The contention of Locke has been confirmed in more recent times, 
and it is now definitely known that isolated organs when perfused with 
Locke's solution can utilize the sugar. For example, Lee and Salant 2 

1 Greene, Chas. VV. : American Journal of Physiology, Vol. II., p. 125, 1899. 

2 Lee, F. S., and Salant, W. : American, Journal of Physiology, Vol. VI., 
p. 61, 1902. 



SERA AND LYMPHS AS PHYSIOLOGICAL SOLUTIONS 301 

found that if parallel gastrocnemius muscles from the same animal 
were perfused, one with Kinger 's solution and the other with Locke 's 
solution, the latter maintained its contractions for a longer time 
and recovered from fatigue more readily. One of the best demon- 
strations of this point has recently been given by Knowlton and 
Starling, 1 who determined the rate of oxidation of sugars by isolated 
mammalian hearts, showing that oxidation not only occurs, but it 
occurs in surprisingly constant proportion per gram of tissue. 

In perfusions with Locke's solution one must not lose sight of 
the fact that well oxygenated fluid must always be used. Body tissues 
quickly use up the interstitial oxygen and must receive a supply 
from the outside. "When mammalian tissues are perfused with inor- 
ganic solutions, i.e., solutions which do not contain the special oxygen- 
carrying pigment, hemoglobin, it is customary to insure oxygen satura- 
tion by bubbling pure oxygen through the artificial solution, or by 
putting the solution under a positive pressure of pure oxygen. 

5. Sera and lymphs as physiological solutions. — In the body 
the blood plasma or the lymph is the normal fluid for the living tissue. 
Naturally when artificial solutions are to be used the ideal fluid 
would be the one in which the tissue has developed. Lymph and 
serum not only contain the inorganic salts which contribute chiefly 
to maintain the constant physical factors, but also numerous traces 
of salts that have been absorbed from the foods or are being excreted 
after more or less oxidation by the tissues. The organic nutritive 
substances are also present in the normal body fluids, the proteins 
and their derivatives, fats, and the various carbohydrates. These are 
the great classes of organic compounds present. Besides, there are 
substances always present in the blood and lymph which are developed 
in response to special conditions which may be impressed upon the 
organism at some time in its life history. These substances are far 
from indifferent chemically, if ignorable physically. One has only 
to refer to the numerous toxins, antitoxins, lysins, etc., which are 
now of such tremendous bacteriological and hygienic interest. There 
are also present those materials derived from the reactions of the 
tissues themselves, i.e., the organ extracts, enzymes, oxidazes, waste 
products, etc. 

The serums, therefore, must vary greatly and fundamentally if 
one takes into consideration their source in different species, and 
in different individuals even of the same species. Because of this 
great variation in composition, particularly as regards the subtler 

1 Knowlton, F. P., and Starling, E. H.: Jour. Phys., Vol. XLV., p. 146, 1912. 



302 ISOTONIC PHYSIOLOGICAL SOLUTIONS 

chemical constituents, it is found that a serum or a lymph derived 
from one animal may be not only not normal, but even toxic to 
another animal. The detail of these factors is discussed in text-books 
on bacteriology, vaccines, sera, organ therapy, etc. Considered from 
the present point of view, a physiological solution that maintains 
through the agency of inorganic constituents normal to sera the 
physical constants will be safer and more nearly inert in those rela- 
tions where it is desired to maintain the pharmacological or thera- 
peutic isotonicity of tissues or organs. 

1 6. Summary. — Physiological saline, 0.9 per cent, sodium chloride 
for mammals, is a valuable agent for increasing the volume of blood. 
It maintains physiological isotonicity, and has the minimum of react- 
ive power. It is a diuretic, acting as a , mild stimulus to the renal 
epithelium and favoring the mechanical separation from the blood 
of the salines and other wastes. It may be introduced into the circula- 
tion of a mammal after excessive loss of blood, in man to the amount 
of one or even two liters. This somewhat lowers the concentration of 
the other salts of the blood, but not to a level that is injurious under 
any ordinary condition. 

Einger's solution is more favorable because it is a more normal 
solution of the salts in the proportions found in blood. An exactly 
balanced Ringer's solution represents the best transfusing fluid, and 
should always be used when available. It maintains isotonicity not 
only of the sodium chloride, but of other salts of the blood. Under 
its influence the tissues continue their protoplasmic life for a surpris- 
ingly long period. 

Locke's solution has all the advantages of Einger's solution with 
the added advantage of furnishing an energj^-giving substance which 
the living tissues, especially the muscular tissues, can immediately 
use. The heart and the skeletal muscles can oxidize the sugar from a 
Einger's solution. 

Lymphs and serum derived from the same species of animal, 
particularly from the same individual, are more nearly normal to the 
tissues than the artificial salines. However, species differences in 
serum, and sometimes individual differences, render the serum toxic. 
This is particularly true where the individuals have been subjected to 
disease or experimental treatment, thereby inducing the changes in 
the serum characteristic of disease. Transfusions of blood, i.e., serum, 
are much more dangerous on these accounts than are transfusions of 
balanced saline solutions. 



L. Detailed Action of Salts Normal to the Body Fluids and 
of Their Chemical Relatives. 

Any discussion of the specific reactions of the salts normal to the 

body fluids leads one at once into that complex of salt action which 

depends on the ionizing properties of these substances. In other 

words, the reactions of a salt in the body are at least threefold, i.e., 

the reactions of the salt molecule as such, the reactions of the positive 

ion, and finally, the reactions of the negative ion. Take, for example, 

the most abundant salt in the blood plasma, sodium chloride. This 

salt dissociates to the extent of some 83 per cent., forming positive 

+ 

Na ions and negative CI ions. The undissociated molecules and each 

of the ions can exert an influence on the living protoplasm. This 
particular salt is considered the most inactive of any present in the 
body, yet what action it has depends more largely upon the influence 
of the ions than upon the undissociated molecules. It is similar 
with other salts, such as potassium chloride, or the calcium and 
magnesium phosphates, or of any one of the numerous related in- 
organic salts. In the case of the potassium or calcium salts, for 
example the chlorides, it is found that the potassium or calcium cation 
is far more reactive with the body tissues than the chloride anion. 

According to the most recent views the salts react chemically 
through the formation of ion proteins. Perhaps to some extent 
molecular proteins are also formed. Such compounds exert their 
influence on the protoplasm both chemically and physically. The 
plasma membrane which covers or bounds the animal cell is a con- 
trolling agency for the diffusion into or from the cell. Attention 
has already been called to the influence of the plasma wall on the 
reactive life of the tissue cell. Variations in the ion protein com- 
pounds are responsible for the character of this wall. With these 
general principles in mind we may take up the detailed discussion 
of the action of the individual salts. 



303 



CHAPTER XL. 

THE SODIUM AND POTASSIUM GBOUP, INCLUDING 
CHLOKIDES, BROMIDES, IODIDES, SULPHATES, 
NITEATES, ETC. 

I. 

The Sodium Salts. 

The salts of the alkali metals are of special interest because of 
the action of their bases. Yet these salts have long been considered 
as the chief agents for maintaining the physical isotonicity of animal 
tissues. 

i. Sodium chloride and the sodium salts. — Sodium chloride is 
normal to the blood plasma and the various lymphs. It is present in 
larger proportion in these fluids than any other inorganic constituent. 
It is assumed that sodium chloride is ionized in the plasma fluids 
just as it is in the simpler solutions. Its action, therefore, can be 
attributed to the reactions induced by the positive sodium and by 
the negative chlorine ions. Sodium chloride in pure solutions in- 
creases the permeability of animal tissues. This point has been 
established in a peculiarly interesting way by R. Lillie. 1 Lillie 
found that if the larvae of the sea worm Arenicola are placed in 
sodium chloride solution isotonic with sea water their muscles 
strongly contract for some seconds, then slowly relax. The cilia of 
the surface not only cease contraction but undergo rapid disintegra- 
tion. Lillie explains this result as due to the increase in permea- 
bility of the epithelial tissue under the influence of the sodium chlo- 
ride. In this case the change in permeability is coincident with the 
stimulative action. In many mammalian tissues, i.e., skeletal muscle, 
heart, etc., it has been shown that sodium chloride increases the 
physiological reactions, in other words is stimulative. When this 
stimulative effect is not prevented by the antagonistic action of 
other ions it may lead to toxic disintegration. This is the explanation 
of the so-called toxic influence of pure sodium chloride. It is greater, 
of course, in the more concentrated solutions. While isotonic sodium 
chloride solutions are of great benefit in medicine and surgery, the 

1 Lillie, R. : "The Physico-chemical Conditions of Anesthetic Action," Science, 
Vol. XXXVII., p. 959, 1913. 

304 



THE POTASSIUM SALTS 305 

concentrated solutions occasionally used are a positive source of 
danger. Several accidents are on record of deaths from the erroneous 
use of concentrated salines as enemas. 

2. The bromides. — Of all the sodium salts the chlorides are the 
most indifferent. The bromides are also relatively indifferent, but 
exert a greater toxic influence than the chlorides. Certain tissues, 
like the muscular tissues, can be kept in a living condition and 
relatively normal in reactions with isotonic sodium bromide solution. 
This solution reacts in very much the same way as physiological saline 
solution. The bromides exert a strong depressing action on nerve 
tissues, reducing the sensitiveness of nerve centers to reflex stimula- 
tion, therefore acting as sedatives. 

3. The iodides. — The sodium iodide is still more toxic than the 
bromide. The toxicity is due chiefly to the iodide anion which is 
strongly irritative to mucous surfaces. Sodium iodide is relatively 
less toxic than some of the other iodides, for example the potassium. 
This is due primarily to the inactivity of the sodium cation. 

4. Sodium nitrate. — Sodium nitrate is still more toxic from the 
action of the nitrate ion. This salt readily diffuses through the 
tissues and sodium in this form is rapidly excreted by the urine. 
The nitrates are, as a matter of fact, stimulative to the renal 
epithelium and to that extent are diuretic. 

5. Sodium sulphate. — Sodium sulphate introduces a new type 
of anion, since the sulphate ion is relatively non-diffusible. The non- 
diffusibility of the anion holds back the diffusion of the cation, 
hence sodium sulphate is not so readily absorbed from the ali- 
mentary canal. This salt is, therefore, a saline cathartic and will 
be discussed more fully under that group. Sodium sulphate is 
strongly stimulative to certain tissues, particularly muscle, both 
striated and smooth. Loeb long ago showed that striated muscle in 
sulphate solutions was stimulated to contractions of a rhythmic 
character. 

6. Sodium phosphate. — Sodium phosphate, Na 2 HP0 4 , is a non- 
diffusible salt, due in this case also to the anion. The salt, as a 
whole, exerts little influence on the body other than that of its 
salt action. 

II. 

The Potassium Salts. 

Potassium is the second most important of the alkaline metal 
bases. Potassium salts, especially the chlorides, bromides, etc., 



306 THE SODIUM AND POTASSIUM GROUP 

readily dissociate in the body fluids. In contrast with sodium salts, 
potassium salts are very active chemically. The potassium cation 
may readily form ion protein compounds and these compounds are 
apparently more fixed than in the case of sodium. Potassium pos- 
sesses less salt action and more chemical action in the body and is 
therefore relatively more important. Potassium salts react strongly 
with muscular tissues, also with nerve, gland, etc. Analyses of 
muscular tissues and of the fixed elements of the blood show a com- 
paratively high percentage of potassium. 

The physiological changes induced by potassium depend upon 
this chemical affinity. The most important of the potassium re- 
actions are those on muscle and on nervous tissues. 

Potassium is of tremendous importance in maintaining a favor- 
able physiological condition for the heart. Numerous investigations 
which have been emphasized in the discussions of physiologically 
balanced solutions go to show that the character of the normal 
contractions of the heart is absolutely dependent upon the presence 
of potassium in the blood and lymph. Potassium reacts here with 
the heart proteins in some sort of opposition to sodium and calcium. 
When the potassium content of Einger's solution is increased, then 
the heart beats slower, relaxes more completely, and contracts with 
less amplitude. If the potassium content is further strengthened the 
heart will cease to beat. Even with the mammalian heart the addi- 
tion of potassium chloride to a perfusion of Locke's or Einger's 
solution is sufficient to bring the contracting heart to a standstill. 
This standstill is quickly removed by the elimination of the excess 
of potassium, showing that the condition imposed upon the heart 
is at least not a strongly fixed chemical combination. This holds 
true for all forms of vertebrate heart that have been investi- 
gated. 

The skeletal muscles contain in their ash a considerable quantity 
of potassium. If the potassium in the 4 lymph and blood circulating 
through skeletal muscle is increased, then the contractions of the 
muscle are weakened and the irritability diminished or lost entirely. 
This point has also been nicely demonstrated by Lillie on the Are- 
nicola larvae referred to above. These larvae swim normally by two 
mechanisms ; first, by the action of trochophoral cilia, which we have 
already seen are readily poisoned by the sodium chloride solutions, 
and second, by the contractions of longitudinal muscles in the body 
wall. Potassium solutions render the muscles inert without inter- 
fering strongly with the action of the cilia. Larvae poisoned in this 



AMMONIUM SALTS 307 

way remain rigid from inactivity of their longitudinal muscles, but 
swim about freely by ciliary movement. 

Undoubtedly potassium is toxic to glandular tissue. This is 
well shown by the toxicity of potassium solutions on the kidney. 

On nerve tissue potassium is a marked depressant. This is borne 
out by the diminished sensitiveness of the peripheral nerves as well 
as the depression noted in the reactive power of the central nervous 
system after large doses of potassium salts. This depression is par- 
ticularly manifest through diminution in the reflexes. In extreme 
toxicity the condition may amount to central nervous paralysis. 

The potassium bromides are much more depressant than the 
chlorides, due to the added action of the potassium ion. In this case, 
since the bromide acts almost specifically on the nervous tissue, it 
follows that the potassium bromides will have a much more profound 
sedative effect on the central nervous tissue. 

Potassium iodides are still more toxic. The potassium and iodine 
ions are apparently particularly toxic for the more generalized tis- 
sues. This salt is used in therapeutics in combating certain in- 
fections, particularly invasions of spirochsete pallida. 

Other salts of potassium, namely, the nitrates, sulphates, citrates, 
and phosphates react in the body in a way comparable to the cor- 
responding salts of sodium. The principal difference is in the fact 
that the depressing factor of the potassium cation is added to each 
salt. Further discussion of this group will be considered under the 
heading of saline cathartics. 



III. 

Ammonium Salts. 

Because of similarity of chemical reaction, the ammonium salts 
will be discussed in connection with salts of sodium and potassium. 
Ammonium chloride is more diffusible than either sodium or potas- 
sium chloride. In fact, in the body the ready diffusibility of this 
salt prevents it from exerting an osmotic pressure where salts of 
sodium or potassium would accomplish this result. Ammonium salts 
are rapidly absorbed and readily diffuse through the body. 

i. The secretions. — Ammonium chloride especially acts as a 
vigorous stimulator of the secretions. This is accomplished through 
the twofold action on the mechanism, i.e., by reflex stimulation and 
through direct excitation of the secretory nerve center. Ammo- 



308 THE SODIUM AND POTASSIUM GROUP 

nium chloride is particularly efficient in stimulating the secretions of 
the respiratory tract and it is on this basis that it has gained its 
reputation as an expectorant. 

2. On the nervous system. — Ammonium salts heighten the 
irritability of the cord and medulla. This is shown by the increased 
reflexes and in some cases convulsion-like spasms. The stimulation 
of the medullary centers shows itself through the various end organs 
connected therewith. The heart is slowed by vagus inhibition, 
respiration is accelerated, and the peripheral blood-vessels are con- 
stricted, though the reaction is mild in all these cases. 

The salts of ammonia have an irritant effect on mucous mem- 
branes, leading to excitation of sensory structures found there. 
These irritations reflexly produce a slowing of the rate of respiration, 
which is antagonistic to the central effects which come later, a more 
pronounced cardiac inhibition, and in some cases bronchial contrac- 
tions. The volatile hydrate of ammonia is particularly irritant to 
the respiratory tract, a fact which is recognized in the use of am- 
monias for reviving persons when in a condition of depressed nerve 
irritability, as for example in fainting, deep anesthesia, etc. 

3. Excretion. — Ammonium chloride and the fixed salts of am- 
monia are eliminated as such through the kidney, but the oxidizable 
forms of ammonia, for example the acetates, citrates, carbonates, etc., 
are converted in the body ultimately into urea and eliminated as 
such. 

IV. 

The Lithium, Rubidium, and Cesium Salts. 

These members of the alkaline metal group are of relative in- 
significance in pharmacology. These bases are not normally present 
in the body except perhaps in traces. On the other hand, they have 
in the past received some medicinal emphasis, especially lithium. 

Lithium salts do not closely resemble either sodium or potassium 
in physiological action, but are rather more comparable to calcium. 
It has long enjoyed a reputation as a saline diuretic. This is due 
largely to its presence in certain mineral waters of therapeutic 
value. It was thought, through work in the middle of the last cen- 
tury, that there was a marked reaction as between lithium and uric 
acid, whereby the latter was increased in solubility in water. A 
more careful investigation of this problem was made by Good, 1 who, 
1 Good, C. A. : Am. Jour. Medical Sciences, February, 1903. 



THE LITHIUM, RUBIDIUM. AND CESIUM SALTS 309 

as a result of a number of experiments on mammals, came to the 
conclusion that lithium is excreted in the saliva, in the stomach 
and intestine, and in the urine, the greater amount being excreted 
by the latter. It makes its appearance in the secretions within a 
few minutes after administration, and may still be detected after 
23 days. Lithium salts do not possess any diuretic action other 
than their salt action, and they are not solvents for uric acid or the 
urates. The lithium salts possess a degree of toxicity to the general 
system, as shown by the symptoms of nausea, vomiting, and diarrhea, 
followed by emaciation, weakness, and even death. These symptoms 
are in part accounted for by marked enteritis indicating an irritative 
or corrosive action on the mucous membranes, particularly of the 
stomach. Good's whole investigation would tend to discredit any 
favorable therapeutic result to be obtained by salts of this metal. 



CHAPTER XLI. 

THE SALTS OF THE CALCIUM AND MAGNESIUM 
GKOUP IN COMBINATION WITH VARIOUS ANIONS. 

The salts of the alkaline earths play a very important role in 
the physiological economy of the mammalian body. These salts not 
only constitute the inorganic constituents of the skeleton and other 
hard parts of the body, but they, particularly calcium, are vitally 
important constituents of the tissues and body fluids. Both calcium 
and magnesium are deposited in the bones of the skeleton as well as 
in epidermal modifications, i.e., the teeth, etc. The adequate supply 
of calcium and magnesium available in the food of animals is essen- 
tially a physiological question. However, attention may be called 
here to the fact that the amount of these salts called for bears a 
very close relation to the state of maturity and growth of the animal, 
as well as the general nutritive factors. Adult animals whose skeletal 
elements are already fixed require only a very small quantity of 
calcium and magnesium in comparison with developing young, or 
with adult females bearing developing young. Deficiency of calcium 
and magnesium in the food leads to distressing conditions of general 
metabolism. From a medical point of view these conditions are 
indicative of malnutrition and are noticed most often in the poorly 
fed children of the tenement districts of our large cities. 



Calcium Salts. 

Calcium salts are present, not only in the bones and hard parts 
of the body, but in all the body fluids and tissues. The ash of the 
various tissues contains a small portion of calcium. It is not easy 
to determine in just what form the calcium is present. Probably in 
many of the tissues and fluids it exists as a calcium phosphate. In 
blood plasma, lymph, and in some of the secretions, as for example 
milk, calcium can be precipitated as a free salt. In the main, how- 
ever, it is assumed that the calcium forms ion proteins in the 
tissues. 

310 



CALCIUM SALTS 311 

Calcium enters into the reactions of many forms of tissue metab- 
olism. Of these may be mentioned blood-clotting, the coagulation 
of milk, the rhythmic reactions of muscular tissue, etc. Calcium 
chloride in the percentage 0.026 is a normal constituent of Ringer's 
and Locke's solutions. It is present in blood plasma in this par- 
ticular concentration, as already referred to on page 300. Although 
calcium probably exists in blood as a phosphate, its reactions have, 
in the main, been demonstrated through the reactions of calcium 
chloride in which the chloride ion is relatively inactive. 

i. Calcium in relation to the heart. — Calcium is a salt necessary 
for the normal contractions of cardiac muscle, a fact that has been 




Fig. 68. — Calcium on the rhythm and amplitude of the ventricular strip of the 
terrapin. The strip was contracting rhythmically in 0.7 per cent, physiological saline. 
At the point marked by the first arrow it was changed to calcium chloride 0.04 per cent. 
in sodium chloride 0.7 per cent. The rate increased from 12 to 27 per minute. On 
returning the muscle to 0.7 per cent, sodium chloride, the amplitude remained higher 
than normal, though diminishing. A bath of potassium chloride 0.06 per cent, in 
sodium chloride 0.7 per cent, entirely suppresses .the rhythm. However, this quickly 
returns in normal physiological saline. New tracing by Miss Pile. 

established through the work of Ringer, Howell, Loeb, and' their 
numerous students. If the amount of calcium in normal saline 
solutions be increased and tested on any rhythmic portion of the 
jheart of the cold-blooded vertebrates, or, in fact, the mammal, it 
will be found that both the rhythm and the amplitude are favored 
by quantities slightly above the normal of the blood plasma of the 
animal. Solutions several times more concentrated than the above 
are always injurious to the tissues, cardiac tissue tending to develop 
a strong tonic contraction with marked predisposition to fibrillation, 
and final loss of fundamental rhythm with inability to relax. The 
latter is a sort of calcium rigor and is removed with some difficulty. 
Calcium forms an indispensable antagonist for potassium salts 
(Howell) and sodium salts (Loeb) of the body fluids. 

2. Calcium in the coagulation of blood. — That calcium was a 
necessary factor in the coagulation of blood was shown by Schmidt, 
and has been confirmed by numerous later investigators. If the 



312 SALTS OF THE CALCIUM AND MAGNESIUM GROUP 

calcium is eliminated from the blood plasma the clotting cannot 
occur until free calcium is again introduced. This is shown in the 
reactions of oxalate plasma. It is obvious that an increase in the 
amount of calcium above the normal favors the coagulation of blood. 
This increase must be slight, however, as an excessive quantity of 
calcium hinders the reaction, hence becomes toxic. 

3. Nerve tissue. — Calcium salts favor the normal reactions of 
nerve tissue. This is demonstrated by the work of Cushing, who 
showed that the sensitiveness of motor nerve endings that have been 
depressed by physiological saline is regained by the perfusion of 
solutions containing calcium in normal amounts. 

4. On metabolism. — That calcium is a factor in metabolism is 
suggested by the behavior of cardiac muscle under its influence. 
Although the matter is not so clearly worked out, it is generally be- 
lieved that the pathological condition of osteo-malacea is dependent 
upon interference with calcium in skeletal metabolism. The matter 
is not a simple lack of calcium, but rather a failure of some factor 
entering into the general reaction, whereby normal metabolism is 
deranged. 

Calcium is present in blood plasma and takes part in the chemical 
changes that occur during blood-clotting. It is also a necessary 
constituent in the formation of casein from caseinogen. Blood-clot- 
ting can be influenced by varying the amount of calcium present in 
the plasma. When calcium precipitants, like the citrates or the 
tartrates, are introduced into the alimentary canal in sufficient quan- 
tity, or guardedly into the circulation, the elimination of the cal- 
cium reduces the coagulability of the blood. The raising of the 
calcium content to increase coagulability, for example to prevent the 
post-partum hemorrhage, has also been attempted. In the last in- 
stance the clinical possibilities are complicated by the fact that 
excess of calcium salts does not aid, but retards the process of coagula- 
tion, which it is sought to facilitate. 

5. Excretion. — Calcium salts are poorly absorbed because of the 
non-permeability of the mucosa of the digestive tube to the calcium 
cation. Those salts of calcium, like calcium sulphate, which contain 
a non-diffusing anion, are, of course, absorbed from the alimentary 
tract with greater difficulty. It follows, therefore, that calcium salts 
taken by the mouth are excreted largely with the feces, never having 
been more than slightly absorbed. But calcium is also excreted in 
small quantities in the urine, and possibly, to some extent, through the 
mucous membrane of the lower reaches of the alimentary tract. 



MAGNESIUM SALTS 313 

II. 

Magnesium Salts. 

Magnesium salts have not been shown to have the intimate re- 
lation to normal metabolic processes which characterize the calcium 
salts. The one exception, of course, is in the large quantity of 
magnesium present in the bones. It is assumed that the magnesium 
is deposited there as a result of growth processes taking place in 
the parenchyma of the skeletal tissue. 

However, magnesium salts, introduced into the body, do have a 
marked influence on certain physiological processes. In the chapter 
on saline cathartics, magnesium action is discussed at length in re- 
lation to the function of the alimentary canal. More recently, 
through the work of Meltzer and Auer, 1 it has been pointed out 
that there is an antagonism between magnesium and calcium salts 
when these are introduced into the circulation. "When, for example, 
magnesium chloride is injected into the circulation, animals so tested 
exhibit a rapid succession of pharmacological phenomena, quickly 
passing to a narcotic-like condition. Rabbits, for example, at first 
show accelerated respiration, then lose muscular control, fall over on 
the floor, and if left alone soon die. If, at the height of the narcotic 
stage, calcium chloride be injected into the circulation, the unfavor- 
able condition is quickly removed and the animal will recover, gain 
its feet, and, in the case of the rabbit, begin eating almost imme- 
diately. This is an extremely striking phenomenon. The explanation 
offered by the authors is that magnesium has a narcotic effect, which 
is anesthetic in character. 

Guthrie and Ryan 2 advocate a different explanation, namely, 
that magnesium has a curare-like effect on motor nerve endings. 
It is this action which destroys the motor control of the animal, 
and when not antagonized, of respiration itself. The introduction 
of calcium into the circulation antagonizes the curare-like action 
and the animal quickly regains control of its skeletal muscles. 

Magnesium, instead of producing a primary anesthesia, in reality 
produces a primary stimulation. This is shown by accelerated res- 
piratory movements and more sensitive reflexes. The stimulating 
effect passes over into a paralysis with the loss of nerve function. 

1 Meltzer, S. J., and Auer, John: American Journal of Physiology, Vol. XIV., 
p. 366. 

2 Guthrie, C. C, and Ryan, A. H.: American Journal of Physiology, Vol. 
XXVI., p. 329, 1910. 



314 SALTS OF THE CALCIUM AND MAGNESIUM GROUP 

So far as the motor apparatus is concerned this undoubtedly, as 
Guthrie and Ryan have emphasized, depends upon the action of 
these salts at the motor nerve endings. They state that: " Results 
show that magnesium salts in common with numerous other crystal- 
loids exert a very decided stimulating action when applied directly to 
the exposed trunk of a sciatic nerve of an otherwise intact frog. In- 
deed magnesium chloride stimulated more powerfully than certain 
other of the substances." 

They are inclined to consider the action of these salts, magnesium 
included, from the standpoint of interference with the oxidations 
during nutritional changes, i.e., as asphyxial in character. 

It is well known that certain toxins, particularly tetanus toxin, 
produce their poisonous effects by a hyperstimulation of the nervous 
motor mechanism. Since this is the point which is depressed by the 
magnesium salts, it is obvious that injections of magnesium chloride 
solutions, under this special toxic condition, would lead to a reduc- 
tion in irritability of the motor end apparatus, i.e., would show 
antagonism against tetanus toxin. This particular fact has been 
made use of in clinical 1 practice in the saving of life after tetanus 
had developed. It apparently gives the body a respite in which the 
tissues may sometimes successfully continue the process of develop- 
ing antitoxins. 

III. 

Barium and Strontium. 

Barium and strontium salts, which belong to the calcium-mag- 
nesium group chemically, have proven quite interesting from a phar- 
macological point of view. Barium, in particular, introduces certain 
changes, comparable in character to the reactions of digitalis. Ba- 
rium has already been treated, see page 174. Strontium, however, is 
of little significance pharmacologically. 

1 Kocher. T.: Correspondenz-Blatt fur Aerzte, Basel; Vol. XLIL, p. 969, 1912. 
Abstract in Journal American Medical Ass'n, Vol. LIX., p. 1490. 1912. 



CHAPTER XLII. 
THE SALINE CATHAETICS. 

Under the heading of alkali metals and the alkaline earths we 
have discussed the physiological action of a number of salts. Some 
of these salts are characterized by their ready solubility and the 
facility with which they are absorbed, while others, sometimes less 
soluble, are characterized by the difficulty with which they are ab- 
sorbed from the alimentary tract. Certain of the salts of this latter 
group produce, by virtue of their physical and chemical characters, 
special actions on the alimentary canal itself. This group is called 
the saline cathartics. The saline cathartics hasten evacuation of 
the bowels. This is accomplished in part by the action of physical 
characters of the salts, but also in part through their chemical 
properties. 

Of the saline cathartics the most important and commonly recog- 
nized are sodium sulphate, known as Glauber's salt; magnesium sul- 
plate, known as Epsom salt; and sodium potassium tartrate, known 
as Rochelle salt. Beside these specific salts any sulphate, citrate, tar- 
trate, or phosphate of sodium, potassium, megnesium, or lithium 
will produce saline catharsis, though of course with greatly varying 
intensities of action. 

I. 
Nature of the Action of the Saline Cathartics. 

An analysis of the nature of saline catharsis must rest upon an 
understanding of the physiology of the alimentary tract. Foods 
that are taken into the alimentary canal undergo a process of solu- 
tion and absorption. The solution is accomplished largely by virtue 
of the action of enzymes introduced into the canal by the various 
alimentary secretions, saliva, gastric juice, pancreatic juice, bile, 
etc. Absorption takes place along the full length of the alimentary 
tract, occurring more rapidly through the wall of the small intestine 
and the upper part of the large intestine. 

Food is moved along the alimentary tract as a result of the 

315 



316 THE SALINE CATHARTICS 

muscular contractions of its walls, especially by the contractions which 
are peristaltic in character. Both secretion and the muscular move- 
ments of the alimentary tract are under complicated nervous regu- 
lation, a part of which at least is carried out through local reflex 
mechanisms. As the algebraic result of the four factors, i.e., quan- 
tity of food ; rate and quantity of secretion ; rate and time of absorp- 
tion; and rapidity of the passage of the food along the alimentary 
tract, there will be a certain quantity of content of a certain con- 
sistency which will reach the lower portion of the large intestine, 
the descending colon. Under the control of the reflexes of defecation 
this residue will pass into the rectum and be evacuated from 
the canal. Anything either normal or pharmacological, which will 
vary one or more of the above four factors, will influence either the 
character or volume, and through these or by other action will 
stimulate the defecation reflex, hence determine the rate of discharge 
of the residue of feces. 

The saline cathartics influence all these factors except the first, 
namely, the quantity of food. This we will undertake to explain. 
The typical saline cathartics, the sulphates, citrates, and tartrates, 
are characterized by non-diffusibility or at least retarded diffusibility. 
When these salts, therefore, are introduced into the alimentary tract 
the first and most striking influence noted is that upon the volume 
of the content of the bowel. Relatively little influence is exerted in 
this regard in the stomach, but a profound influence in the intestine, 
especially the small intestine. The presence of non-absorbable ions 
gives a permanent condition producing osmosis, which in this instance 
will tend to draw water from the mucosa into the tube of the intestine. 
Particularly is this true while the concentration of the salts is hyper- 
tonic to the body fluids and tissues. In fact, the rate of transfer of fluid 
is in fairly close proportion to the concentration of the non-absorbable 
ions. The sulphates, for example, are absorbed slowly and with marked, 
difficulty. They produce, therefore, a withdrawal of water from 
the blood and tissues. This increases the volume of the alimentary 
content. If the volume becomes great enough to mechanically distend 
the intestine that will in itself stimulate the muscular mechanism 
and therefore cause an increase in the peristalses, thus hastening the 
driving of the content down the alimentary tube. The net result 
is that the volume of food, fluid, etc., is passed along the alimentary 
canal more rapidly than normally and reaches the rectum in a more 
fluid form. 

The rate at which the above physical factor acts is largely de- 



NATURE OF THE ACTION OF THE SALINE CATHARTICS 317 

pendent, so far as the particular saline is concerned, upon the 
amount and concentration of the salt used. There is another factor, 
however, and that is the condition of the body as regards its normal 
content of water. Experiment-ally it is shown that if an animal be 
restricted in its allowance of water and fed a comparatively dry 
food for say 24 hours or more, its tissues become somewhat hyper- 
tonic. Under this condition of the body the non- diffusible saline 
cathartics act more slowly, or fail of purgation. 

All substances which extract water from the mucous membrane 
of the alimentary tract have some degree of irritant influence on 
the mucosa. This irritant influence may vary greatly in intensity, 
depending not only upon the character of the salt itself, but also 
upon its concentration, and upon whether or not the stomach and 
intestine are relatively free of food at the time, i.e., intimacy of 
contact. A concentrated solution of a cathartic salt, or still better, 
an undissolved salt, will withdraw water from the mucosa of the 
stomach, where the salt first comes to rest for a time, so rapidly that 
the cells become quite hypertonic. This produces local irritation, 
and in many cases leads to marked reflex stimulation, accompanied 
by a burning sensation, sometimes nausea and vomiting. But this 
action of the saline cathartics is not vigorous enough to produce an 
inflammatory process. The action of this factor of irritation, es- 
pecially in the duodenum and the upper lengths of the small intes- 
tine, may lead to quite profound reflex stimulation of the peristaltic 
mechanism of the canal. This increase in peristalsis may be great 
enough to lead to evacuation of the bowels within 15 or 20 minutes 
after the salt is taken, whereas an evacuation from the pure osmotic 
action would not ordinarily take place under 2 or 3, and usually 
more hours. 

Any irritation of the gastric mucosa will inevitably reflexly 
accelerate the secretions not only of the salivary, but also of the 
gastric glands. Probably the pancreatic gland, too, is reflexly stimu- 
lated by irritation of the gastric and of the intestinal mucosa. It 
follows that there will be a great increase in the total volume of the 
gland secretions poured into the alimentary tract, and these will 
add to the quantity of the content. Ordinarily the sum total of the 
volume of the secretions of the alimentary tract will amount to 
some 3 or 4 liters per 24 hours, i.e., saliva 800 to 1000 cc, gastric 
juice 1000 to 2000 cc, bile 500 to 700 cc, pancreatic juice 600 to 
800 cc. Under the stimulating effect of a concentrated cathartic 
these quantities are correspondingly increased. 



318 TEE SALINE CATHARTICS 

We have, therefore, as a result of the general action of the saline 
cathartics the possibility: 

1. of lowering the rate of absorption. 

2. of extracting fluid from the mucous membrane. 

3. of stimulation of the alimentary glands to increased secretion. 

4. of stimulation of the peristaltic movements, thus hastening 
the content along the tube. 

5. of stimulating the reflex mechanisms of defecation. 

A salt that typically produces the first four of these processes will 
of course more quickly lead to purgation. 

i. Sodium sulphate. — Glauber's salt or sodium sulphate disso- 
ciates into the readily diffusible sodium cation and the almost non- 
diffusible sulphate anion. If solutions of isotonic concentration are 
taken by way of the mouth they hinder the normal process of absorp- 
tion. This factor alone would produce a seemingly more liquid con- 
tent of the intestine, which is, of course, only a secondary result of 
the failure of normal absorption. But hypertonic sodium sulphate 
solutions cause some positive abstraction of fluid from the alimentary 
mucosa. The result is that there is an addition to the amount of 
fluid present in the alimentary content instead of a decrease as in 
normal absorption. The net results of the action of this positive 
factor is a mild catharsis, even were no other factor involved. 

However, sodium sulphate stimulates the neuro-muscular mech- 
anism involved in alimentary peristalsis. This can be shown if one 
performs the Moreau experiment by introducing sodium sulphate 
into the primary loop of the intestine. In this instance he will find 
that vigorous peristaltic contractions are set up almost immediately, 
in fact making it difficult to fill the loop with the fluid without ex- 
ternal pressure. This is in contrast to the behavior of other cathartic 
salts in this regard. It is this vigorous intestinal contraction that 
produces the griping pain so often noted when Glauber's salts are 
used therapeutically. The effect is due to the direct stimulation 
of the mucosa, which leads to a reflex through the local nervous 
mechanism controlling the contractions of the intestinal wall. 

Under the above discussion the action of sodium sulphate is ex- 
plained as due to two processes: osmotic extraction of fluid from the 
mucosa and increase in physiological activity of the muscular walls. 
Hertz, however, has revived the theory of stimulation, which was 
advocated by MacCallum some years ago. Hertz's x studies indicated 

1 Hertz, A. F., Cook, F., and Schlesinger, E. G.: Guy's Hospital Reports, 
Vol. LXIIL, 1901. 



ACTION OF SODIUM SULPHATE 



319 



that watery stools from sodium sulphate did not contain an increase 
in the sulphate ions, in fact showed that the sulphates excreted 
by the feces were found only several hours after the first watery 
stool. On the other hand, there was a marked excretion of sulphate 
by the urine within eight hours after the taking of the salt. These 




Fig. 60. — The effect of sodium tartrate upon the structures of the kidney. 
Necrosis involves every convoluted tubule. The glomeruli are normal. From Underhiil, 
Wells, and Goldschmidt. 



factors he says indicate that, " The semi-fluid character of the first 
stool was not a result of water being extracted into the intestine by 
the salt." He emphasizes the point of view of Aubert, that after 
absorption the salt acts on the neuro-muscular mechanism of the 
colon rather than on the small intestine, producing an increase of motor 
and secretory activity. The sodium sulphate influence on intestinal 
movements is admitted and strongly emphasized, but that it is an 






320 THE SALINE CATHARTICS 

effect occurring only after absorption is at present a debatable 
question. 

2. Sodium potassium tartrate. — The double salt of sodium and 
potassium tartrate owes its cathartic action to the low diffusibility 
of the tartrate anion. The cathartic action of this salt is milder 
than that of sodium sulphate. It does not produce such vigorous 
intestinal muscular contractions, hence is relatively bland in its 
effects. The anion in this case is slowly absorbed, but unlike most 
organic acid radicles, is not readily oxidized in the body. It is 
slowly excreted by the kidney unchanged. But while the tartrate is 
unchanged, one cannot say as much for the kidney after the tartrate 
has passed. Underbill, "Wells, and Goldschmidt 1 have quite recently 
shown that tartaric acid is vigorously toxic for the renal tubules, pro- 
ducing marked nephritis with extensive necrosis. Curiously enough 
the glomerular capsules escape the injury, apparently due to the 
fact that they are not the main excretory organ for this injurious 
organic acid. The authors have given both morphological and physio- 
logical evidence for the contention offered. More recently Pearce 
and Ringer 2 have re-investigated the action of the tartrates in the 
production of experimental nephritis. Their conclusions from ex- 
periments on dogs are expressed in the following quotation : — 

" The administration to the dog of tartrates, by mouth, intra- 
peritoneally or subcutaneously, causes a severe renal disturbance, 
characterized by albumin and casts in the urine and diminished flow 
of urine or complete anuria. The urine passed before complete sup- 
pression is water clear of low specific gravity, and the solid con- 
stituents are greatly decreased. The most striking histological change 
in the kidney is necrosis of the convoluted tubules, with fatty changes 
in the loops of Henle and sometimes also in the collecting tubules. 
Exudative glomerular lesions occur in about half the animals with 
tubular lesions. 

" The mode of administration does not influence the character of 
the renal lesion, except in as much as diarrhea, following administra- 
tion by mouth, may cause rapid removal of the salt from the in- 
testine, and thus by reducing the amount of absorption prevent the 
severer types of lesion." 

It has not yet been determined how toxic the tartrates are for 

1 Underhill, Wells, and Goldschmidt: Journal of Exper. Medicine. Vol. XVIII., 
p. 317, 1913. 

2 Pearce, R. M., and Ringer, A. I.: Journ. Medical Research, Vol. XXIX., 
p. 57, 1913. 



ACTION OF MAGNESIUM SULPHATE 321 

the alimentary mucosa. The current view that they are mild and 
non-toxic should now be questioned on account of the action demon- 
strated on the renal parenchyma. It is probable that the mucosa does 
not escape an influence comparable to that observed in the kidney. 
If so its cathartic action of sodium and potassium tartrate more 
nearly approaches the character of that of the vegetable purgatives 
than other members of this group. 

3. Magnesium sulphate. — Magnesium sulphate owes its saline 
purgative action to the slow diffusibility of both the positive mag- 
nesium and the negative sulphate ions. Magnesium is absorbed from 
the alimentary canal with difficulty, and we have already seen that 
the sulphate ion is greatly retarded in its passage through the in- 
testinal wall. Therefore the presence of this salt produces a very 
effective condition of interference with the ordinary absorptive 
process. The content of the alimentary tube is kept relatively con- 
stant in fluid during its passage toward the colon. If the magnesium 
sulphate is comparatively concenerated, then the hypertonic solution 
will draw fluids from the intestinal mucosa, as has already been 
described. The salt is not strongly irritant to this membrane and 
we may assume here a more vigorous physical action than with other 
members of the salts. The intestinal content reaches the colon in a 
more fluid form and in greater bulk and this leads to the cathartic 
action. The comparatively non-irritant qualities of magnesium sul- 
phate make this salt a sufficient one for mild catharsis. If highly 
concentrated solutions in too great amount be used, then there is greater 
absorption of the salt itself, a process that may be sufficient to carry 
enough into the circulation to produce its specific depressant action. 
The systemic action has already been described, page 313. "When such 
increased absorption occurs there is a tendency to suppression of intes- 
tinal peristalsis and to the appearance of a degree of the toxic action 
of the magnesium ion, as manifested on the respiratory mechanism 
and the skeletal muscular complex. 

In the case of magnesium sulphate a process of precipitation and 
elimination of the magnesium cation goes on in two ways; first, 
through the formation of carbonates from the carbon dioxide con- 
tent of the blood, and second, by the formation of magnesium soaps 
from the fatty acid liberated during fat digestion. Each of these 
compounds reduces the magnesium to a molecular basis. The sul- 
phate ion, under these conditions, is slowly absorbed and combines 
with hydrogen ions derived from the blood and tissues to form acids, 
or with the alkaline bases to form soluble sulphates, which are ex- 



322 THE SALINE CATHARTICS 

creted through the kidney. Either process tends to work against 
the alkalinity of the blood and toward relative acidosis. 

MacCallum * has studied the cathartic action of the magnesium 
salts by the method of hypodermic injections. He came to the con- 
clusion that the magnesium sulphate produced its cathartic effects 
through the direct stimulation of the secretory nerve mechanism, 
controlling the flow of fluids into the colon and the mechanism of 
defecation. He describes the appearance of catharsis as occurring after 
a constant and rather short time interval, thus throwing doubt on the 
osmotic properties and relations described above. Hertz has to some 
degree supported this view of saline catharsis in general as previously 
mentioned. However, this work of MacCallum 's has been questioned 
more recently, and it has been suggested that his position is erroneous, 
largely through the unfortunate choice of rabbits as investigation 
animals. Babbits are ill adapted to this type of experiment. One 
may, in the circumstances, take a conservative position. 

The introduction of magnesium sulphate by way of the mouth 
is said to be favorable in certain types of edema. In fact, magnesium 
sulphate may, through its vigorous extraction of fluid from the 
mucosa, quite strongly reduce the water content of the tissues. Even 
the normal tissues may be rendered hypertonic. If the tissues are 
already hypotonic from edematous processes, then saline catharsis 
favors the elimination from the body of such injurious materials as 
toxins, poisons, etc. The carrying out of the body of a large amount 
of fluid by either the alimentary canal or the kidney will of neces- 
sity wash out large quantities of such special materials. If the toxins 
are derived from the putrefying masses in the alimentary canal, 
then, of course, the beneficial influence consists largely in removing 
the source of the injurious agency. It is this latter factor which is 
utilized by the clinician in the course of many infectious conditions 
of the alimentary tract. It would seem, at first sight, that if the 
tract were already inflamed and in the over-active condition ex- 
pressed by diarrhea, the giving of a purgative of any kind would be 
contraindicated. But the mild saline purgatives do not add much 
to the pathological inflammatory process and they have the further 
advantage that their action begins at the upper or duodenal lengths of 
the alimentary tract, hence they tend to dislodge and remove the putre- 
fying or infecting agency wherever it may be located. The specific poi- 
sonous action of the magnesium ion of magnesium sulphate and the tar- 
trate ion from the tartrates justified the caution against the use of these 
1 MacCallum: American Jour. Physiol., Vol. X., 1903. 



THE SALINE CATHARTICS AS ENEMAS 323 

drugs in conditions of marked inflammation or possible necrosis of the 
alimentary canal. Where the protective mucous membrane of any sur- 
face has for any reason been injured there is always the danger of the 
absorption of such toxic ions, an absorption that may produce very 
unfavorable, even dangerous, results. 

4. The saline cathartics as enemas. — The discussion of the 
action of the saline cathartics presented above is based on the changes 
which follow their introduction into the alimentary tract by way of 
the mouth. Clinically speaking, there are many conditions in which 
evacuation of the bowel is desired, yet in which this route is un- 
favorable or prohibited. Rectal injections or enemas are utilized 
under these conditions. Pure cold water is one of the most active 
agencies for this purpose. It stimulates mildly and therefore sets 
up rectal peristalsis, thus producing evacuation. On the other hand, 
if the content of the rectum is relatively dry and firm, a slow absorp- 
tion of water by the fecal matter may be desired in order to soften 
and facilitate the evacuation. In this case enemas of any of the 
above saline cathartics, or, in fact, of the more mildly acting saline 
soaps, may be used. Sodium sulphate favors the development of 
peristalsis, which may in some cases amount to rather violent tenes- 
mus. Magnesium sulphate facilitates a relatively slow secretion of 
considerable fluid into the bowel, the consequent softening of the 
content, and the development of mild defecatory impulses. The use 
of salines as enemas rests chiefly on the factor number five, previously 
mentioned, i.e., the stimulation of some portion of the reflex mechan- 
ism controlling the act of defecation. 

For agencies which act particularly on the large intestine, the 
reader is referred to the discussion of the vegetable purgatives. 



CHAPTER XLIII. 

ALKALIS AND ACIDS. 

The displacement of the usual salt anions, i.e., chloride, bromide, 
sulphate, etc., by hydroxyl, OH, and the substitution of the usual 
salt cations, i.e., sodium, potassium, magnesium, etc., with hydrogen, 
H, gives to these substances properties whereby they are peculiarly 
toxic. The alkalis, especially in the stronger solutions, are particu- 
larly caustic. The acids, on the other hand, are many of them pre- 
cipitants to proteins, and in more concentrated solutions also caustic, 
therefore toxic. 



Alkalis. 

The alkalis of most general interest are the hydrates of sodium, 
potassium, ammonium, calcium, etc. The carbonates of these bases 
are alkaline in reaction, but this is due to the fact that the dissociated 
carbonate anion tends to combine with one hydrogen of water, set- 
ting free hydroxyl ions. Hence in both cases the alkalinity and, 
therefore, the caustic action is due to the hydroxyl ion. The action 
of the cation of the alkalis is the same as in the corresponding salts 
which have already been discussed. 

A mild degree of alkalinity is normal to living protoplasm. The 
physiological fluids are slightly alkaline in reaction and blood plasma 
from the presence of sodium carbonate and disodium phosphate nor- 
mally has the percentage of alkalinity 182 to 218 mgr. NaOH per 
100 cc. of blood, Simon. The blood plasma holds tenaciously to the 
alkaline reaction. The chemical reactions of protoplasm take place best 
under this condition of mild alkalinity. If the alkalinity is overcome 
and the reaction reduced to acid, then the physiological processes of 
protoplasm are hindered or cease altogether. A slight increase in 
alkalinity above the normal limit hastens physiological activity. 
Hydroxyl ions promote hydration processes in the tissues, hence the 
favorable action just mentioned is in all probability due to a cor- 
responding increase in the fluidity and permeability of the tissues. 

The favorable limits or range of increase in alkalinity are re- 

824 



ALKALIS 325 

stricted. The higher concentrations tend to produce injurious 
hydrolysis of the tissues. The alkalis are therefore peculiarly caustic. 

i. The cauterizing action of the alkalis. — Sodium hydrate in 5 
per cent, solution applied to the skin quickly leads to hydrolysis of the 
corneous layers. The solution readily penetrates to the deeper layers 
of the corium, producing dissolution and corrosion. The concen- 
trated solutions of the hydroxides kill, but do not dissolve the 
tissues until the alkali is diluted, at which time solution quickly takes 
place. Many violent accidents constantly occur from this action of 
the alkalis. If the corrosive agent is not removed or neutralized, 
then it continues to penetrate deeply into the tissues and may lead to 
the death and dissolution of extensive areas. 

2. The physiological action of the alkalis. — Alkaline salts of 
the hydrates produce changes in physiological responses of the body 
in two ways. One is through the mild stimulation of reflex nervous 
mechanisms, especially in the mouth and gastric region. The second 
is through the change in the degree of alkalinity of the body proto- 
plasm. When alkalis, carbonates or hydrates, are taken by way of 
the mouth, the first effect is a neutralization of the acid gastric juice, 
accompanied by a mild reflex stimulation of the gastric mucosa. 
When these solutions pass into the intestine they favor the normal 
alkalinity that already exists in this region. Alkalis are readily 
absorbed. When they pass into the blood stream and are distributed 
throughout the body they favor protoplasmic processes chiefly through 
their favorable influence on oxidations. Muscles contract more vigor- 
ously, glands secrete more efficiently, as for example the increased 
quantity of the bile. 

However, once in the circulation, the added alkalinity is quickly 
adjusted by virtue of the ability of the tissues to neutralize any 
marked variation from the normal per cent, of alkali or acid. As 
an example, one needs only to note the excess of carbon dioxide con- 
stantly being formed, which can take up and balance any increase in 
the alkalis. The alkalis arc readily excreted through the kidney, 
and it is said that uric acid excretion is increased by the alkalis. 
The body can handle considerable amounts of alkali, enough to 
reduce the normal acidity of the urine or even produce a slight 
alkalinity. Clinicians utilize this factor in combating those condi- 
tions of hyperacidity present in certain types of acidosis. 



326 ALKALIS AND ACIDS 

II. 

Acids. 

The mineral and the organic acids may be considered together, 
though they vary strikingly in certain properties. On the whole, the 
acids are generally toxic to protoplasm. The mineral acids are 
peculiarly so. Although hydrochloric acid is a normal constituent 
of at least one body fluid, i.e., gastric juice, yet it is one of the most 
toxic of the group. However, in the percentage represented in 
the gastric juice the hydrochloric acid is mildly antiseptic. In 
fact, this antiseptic action is normally great enough to destroy large 
numbers of bacteria, which would otherwise enter the lower part 
of the alimentary tract, and become positive sources of disease in 
the body. Nitric acid is strongly oxidative and precipitative, as is 
also sulphuric. Both are corrosive in concentrated form. 

If the stronger mineral acids are applied to the skin they produce 
at once precipitation of the protein constituent and death of the 
epidermis. The precipitation of the tissues tends to hinder the further 
diffusion of the acid, yet when not neutralized there is slow diffusion 
and destruction of the deeper tissues. The process is violently irri- 
tant, hence there is great pain from the continued hyperstimulation, 
often leading to nervous shock and collapse. The mineral acids exert 
the same type of cauterizing action on the mucous membranes as on the 
skin, that is, there is a tendency to precipitate proteins, resulting 
in the forming of layers or coats, which delay the diffusion of the 
acid into the deeper parts. The reflex effects of this type of corro- 
sion on the mouth and alimentary tract are tremendous. There 
occurs an over-stimulation of the great medullary centers leading 
ultimately to vascular dilation, cardiac irregularity, and in some 
cases collapse with the accompanying shock. 

The organic acids are also strongly irritative, but not so corrosive. 
In the body they more quickly become diluted and certain of the 
acids are oxidized; for example, acetic, citric, etc. Among this 
group tartaric acid is not readily oxidized, therefore its irritative 
properties continue up until the time of complete elimination. 

i. The action of dilute acids. — The normal 0.2 per cent, hydro- 
chloric acid present in the gastric juice performs several interesting 
functions. These have been described by Cannon in his discussion 
and demonstration of the acid closure of the pylorus and of the 
cardia. The presence of 50 cc. or so of 0.2 per cent, hydrochloric 



THE ACTION OF DILUTE ACIDS 327 

acid suddenly introduced in the upper end of the duodenum leads 
to local reflex contraction of the pyloric sphincter, and, therefore, 
closure of the pylorus. The cardiac sphincter reacts in much the 
same way. Both instances are examples of reflex stimulation of 
sensory structures in the mucosa by the dilute acid. Dilute acids 
act in like manner in other parts of the alimentary tract, as for 
example the stimulating effect of acetic or citric acid in the mouth. 
A taste of lemon juice is sufficient to set up a quite vigorous secre- 
tion of saliva. The same reflex mechanism can be set into action by 
dilute inorganic acids, hydrochloric acid, sulphuric, etc. The fruit 
acids play an important physiological and pharmacological role in 
the body by virtue of this property. 

Dilute acids, both organic and inorganic, are readily absorbed, 
possibly in part by virtue of the formation of acid proteins. When 
introduced into the circulation the acids meet the alkalis resulting 
from tissue metabolism and are either oxidized or neutralized. For- 
tunately the body possesses a complex and adequate mechanism for 
doing this very thing. A quantitative excess of acid becomes in- 
jurious since it leads to the precipitation and destruction of proteins 
and a corresponding freeing of basic nitrogen for the elimination 
of the acid. However, before this takes place a considerable 
excess of acids may be taken care of by the body by virtue of the 
conversion of neutral salts into acid salts, such as the conversion of 
sodium carbonate into bicarbonate, monohydrogen phosphate into 
dihydrogen phosphate, etc. 

Any free ammonia in the body fluids or tissues fixes acid ions, 
forming the corresponding salts. Ammonia nitrogen is always an 
available base for neutralizing excess of acid ions. Acids, therefore, 
tend to increase the ammonia output in the urine, and in direct ratio 
to reduce the urea output by the equivalent interference with the 
usual formation of urea of ammonia wastes. 

The kidney excretes acids largely as acid salts. If the quantitj 7 
is great enough to lead to an excess of acid there will be a positive 
irritation and necrosis of the renal epithelium, which, of course, is 
unfavorable. 

The organic acids, like acetic, citric, etc., are oxidized by the body. 
Under normal conditions, therefore, these acids are eliminated with- 
out injury to the organism. Tartaric acid is an exception in the 
group. If for any reason the oxidative power of the body is reduced, 
then a portion of the organic acids may pass through the body in- 
sufficiently oxidized and prove injurious. The therapeutic condi- 



328 ALKALIS AND ACIDS 

tion of acidosis is a condition in which, for reasons of incomplete 
oxidations an excess of acids occurs. These acids may be derived 
from the incomplete oxidation of fats on the one hand, or of carbon- 
hydrates on the other, as well as from acids taken into the body from 
without. 



CHAPTER XLIV. 
OXIDIZING AGENTS, OXYGEN, PEROXIDE, ETC. 



Oxygen. 

That oxygen is necessary to the life of animal tissues was long 
ago established. The part played by oxygen in respiration in general 
was made known by the ancient experiments of Lavoisier and of 
Priestly. In the mammalian body the amount of oxygen is kept 
relatively near the saturation point in the animal fluids. That is, 
considering the partial pressure of oxygen in the air it is found 
that the amount of oxygen in the blood plasma and in the body 
lymphs is high and comparatively constant. It is assumed in physiol- 
ogy that the interstitial oxygen is held in some form of fixed compound 
with the living protoplasm. Such a favorable condition is made 
possible only by the development of respiratory pigments, in the 
case of man and mammals the hemoglobin. 

Experiments on isolated tissues readily demonstrate the necessity 
for oxygen. Loeb has given special emphasis to this point, calling 
attention to the fact that if free oxygen is removed from about 
developing eggs of marine invertebrates the developmental process 
slows or ceases. It is immaterial whether the oxygen is removed 
directly or its utilization prevented by the presence of some salt, 
as for example sodium or potassium cyanide. The various methods 
for studying the isolated organs, such as portions of the intestine, 
uterus, etc., all provide for an adequate supply of free oxygen in 
contact with the tissue. When this free oxygen is withheld, then 
the normal physiological processes are reduced or tend to disappear. 
Under ordinary physiological conditions an oxygen environment, rep- 
resented by the atmospheric pressure at ordinary levels, is sufficient. 
"When this percentage is reduced by extreme heights, as in aerial 
navigation, it may happen that the percentage of free oxygen is 
below the necessities of the body and unconsciousness and death may 
result. 

A diminished percentage of oxygen acts as a stimulus to the 
nervous tissue, particularly the respiratory center, though one must 
remember that the condition is usually associated with an increase of 



330 OXIDIZING AGENTS, OXYGEN, PEROXIDE, ETC. 

carbon dioxide, which stimulates the respiratory center even more 
strongly. This particular center is, in a way, a special case. The 
accelerating influence of oxygen-lack occurs only within restricted 
limits. If the deficiency of oxygen is too great, then even the res- 
piratory center loses its irritability and becomes paralyzed. The 
recent work of the Pike's Peak Expedition 1 served to show that 
there is a certain amount of adaptation which the body can make 
to rarefied atmospheres. If, under such an environment, physical 
exertion is reduced to a minimum life is maintained with a much 
lower percentage of oxygen in the air than would otherwise be 
required. 

i. Effects of increase of oxygen. — The respiration of pure 
oxygen does not increase the amount of available oxygen in the body 
to the extent that one would suppose. Normal respiration of ordi- 
nary air is adequate to saturate about 0.9 the hemoglobin, hence we 
have only the remaining 0.1 as a variant for increasing the amount 
of oxygen carried into the tissues. Of course in certain diseases 
or in certain environmental conditions of a physiological nature there 
is great reduction in the total amount of oxygen secured by absorp- 
tion. Under these circumstances the substitution of oxygen for ordi- 
nary air will prove favorable. The higher percentage of oxygen 
respired will facilitate the amount absorbed by increasing the differ- 
ence in the absorption level. Thus, in cases where the active portion 
of the lung is reduced to a fraction of its normal, there might 
possibly be enough oxygen absorbed from the pure gas to supply the 
physiological needs of the body, where such would fail if ordinary 
air were breathed. 

In the mammalian body the percentage of oxygen in the 
blood plasma and in the lymph of the capillary bed is below the 
saturation point. In the tissue itself it is generally assumed that 
the free oxygen is fixed as soon as it enters the protoplasm. It has 
been stated above that the cutting off of the supply of free oxygen 
quickly stops protoplasmic activity. Its readmission leads to a re- 
establishment of metabolism, a point proven in the development of 
fertilized egg cells, and more fully elucidated by Loeb. If pure 
oxygen is made to saturate the lymph bathing a tissue, that will 
facilitate or stimulate the intensity of physiological processes. Though 
the excess of oxygen in contact with protoplasm increases oxidative 

1 C. G. Douglas, J. S. Haldane, Y. Henderson, and E. C. Schneider: Philo- 
sophical Transactions of the Royal Society, Series B, Vol. CCIIL, pp. 185-318, 
1912. 



THE PEROXIDES 331 

processes it must not be forgotten that excess of oxygen in the respira- 
tory gases does not necessarily provide this excess around the tissue 
itself. It seems that this point may be over-emphasized because of 
the general assumption of the contrary proposition. 

II. 

The Peroxides. 

Of all the oxidizing agencies the peroxides are probably the 
simplest and most active. Hydrogen peroxide, H 2 2 , serves as an 
ideal representative of the class. The oxidizing power of hydrogen 
peroxide on living tissues is recognized in the therapeutic use of 
the chemical for sterilizing and disinfecting purposes. A solution 
of 1 to 10,000 in water is sufficient to kill ciliate infusoria in from 15 
to 30 minutes (Paul Bert). Hydrogen peroxide in the stronger 
solutions- prevents development and leads to the destruction of many 
forms of bacteria, in particular the anaerobes. 

Hydrogen peroxide brings about oxidation in certain types of 
chemical reaction where the presence of ordinary atmospheric oxygen 
fails of reaction. In the human body there are reductions which 
occur in the presence of normal protoplasm in particular groups of 
chemicals the oxidations of which cannot be produced outside of the 
body except in the presence of hydrogen peroxide. This has led 
physiological chemists to certain theories of auto-oxidation. These 
views, together with an illustration, are presented distinctly in the 
following quotation from Dakin x : 

"It is generally believed that living cells contain labile sub- 
stances capable of taking up molecular oxygen from the oxyhemo- 
globin of the blood with the formation of unstable peroxides possess- 
ing marked oxidizing properties. Schonbein, and later Bach, have 
shown that a large number of substances of the most diverse kinds 
when undergoing slow oxidation yield substances giving the reactions 
of hydrogen peroxide. 

" In addition, Baeyer and others have actually isolated a number 
of superoxides and substituted hydrogen peroxides derived from many 
different types of aldehydes and ketones. It certainly appears likely 
that substances of this type are concerned with the oxidations of 
substances in living tissues, and indeed such knowledge as has been 

1 Dakin, H. D. : Oxidations and Reductions in the Animal Body. New York, 
p. 7, 1912. 



332 OXIDIZING AGENTS, OXYGEN, PEROXIDE, ETC. 

derived from a study of the various oxidations effected by enzymes 
found in the living cells strongly supports such a supposition. The 
occurrence of certain metallic salts, especially those of iron and 
manganese, in conjunction with certain vegetable oxidases, and the 
extraordinary influence they have upon the ferment activity, is paral- 
leled by the catalytic action of these same salts in accelerating oxi- 
dations in vitro by means of hydrogen peroxide. 

" "Within the last few years other evidence has been secured in 
favor of the belief of the formation of unstable superoxides as the 
active oxidizing reagents of the body. If the hypothesis of super- 
oxide formation is correct, one would expect a certain similarity 
between the oxidations effected in the body and those brought about 
by the simplest superoxide, namely hydrogen peroxide. As a matter 
of fact, an extraordinarily close similarity as regards the types of 
reaction exists between the two sets of phenomena. Thus the normal 
saturated fatty acids in the body undergo oxidation in the /^-position, 
butyric acid yielding acetoacetic acid — a truly remarkable change. 

" Hydrogen peroxide alone of all the various chemical oxidizing 
agents brings about precisely the same reaction : — 

CH .CH .CH .GOOH — * CH .CO.CH .COOH" 

3 2 2 3 2 

Butyric acid Acetoacetic acid 

A number of vigorously acting chemical oxidizing agents are very 
toxic to living protoplasm. Of these may be mentioned chromic acid, 
permanganic acid, chlorine, bromine, arsenic acid, phosphorus, all of 
which owe their extreme toxicity to the formation of fast oxygen 
compounds. These are outside the field of oxidizing agents in the 
physiological sense, and are discussed under the head of Toxic Action 
in the appropriate place. 



M. The Salts of the Heavy Metals. 

CHAPTER XLV. 

THE GENERAL EEACTIONS OF SALTS OF THE 
HEAVY METALS. 

Salts of metals, roughly classified pharmacologically as the heavy 
metals, have certain general reactions which influence the functions of 
the mammalian body. There is no strict line to be drawn from the 
pharmacological point of view as regards the salts included in this 
group. But the more important metals included in the discussion 
are: Copper, lead, zinc, sulphur, phosphorus, iron, mercury, silver, 
and bismuth. Beside these, a number of other members of the chemical 
group are pharmacologically active but in no way peculiarly distinct 
from the action of the members of the group chosen, and of no special 
practical significance. Chiefly for these reasons they are not in- 
cluded in this discussion. 

i. The formation of metal albuminates. — "What changes the dif- 
ferent salts of a given metal will induce and the comparisons of the 
reactions of salts of the different metals depend upon several chemical 
and pharmacological factors which will be briefly discussed. 

The most typical reaction of the salts of this group consists in the 
formation of albumin compounds. Most of the heavy metals react 
with different proteins and protein-like substances to form the cor- 
responding albuminates. In this regard the organic substances act 
like acids, displacing the acid in combination with the metal. For ex- 
ample, lead acetate in contact with protoplasm forms a soluble lead 
albuminate of the protein moiety of the protoplasm, at the same time 
setting free acetate with the coincident formation of acetic acid. The 
same may be illustrated by silver nitrate, mercuric chloride, etc 

The intensity and rapidity of this reaction depend upon the 
solubility and the ionizing properties of the particular salt. If 
the salt is very soluble and ionizes freely, it will produce a more 
vigorous and rapid precipitation of protein and a corresponding 
greater pharmacological reaction if that protein is a constituent part 
of living protoplasm. Organic compounds of the metals are for this 

333 



334 REACTIONS OF SALTS OF THE HEAVY METALS 

very reason less intense in their actions than inorganic compounds. 

In general the reactions of the salts of the heavy metals are 
astringent, stimulative, irritant, or corrosive. The action is not en- 
tirely due to the metal factor, but in some forms it is partly due to 
the action of the acid ion liberated. 

The metal albuminate is in many instances soluble in excess of 
the albumin. Some organic compounds, as metal vitellinate, are gen- 
erally soluble. Most metal albuminates when in small quantity are 
soluble in excess of the albumin. The different metals vary greatly 
in this regard. Albuminates of mercury are rather more readily 
soluble in excess of the albumin than are, for example, silver albumi- 
nates. Another factor in the human body that greatly influences the 
solubility of the metal albuminates is the presence of the salts of the 
alkaline earths. An insoluble excess of albuminate of mercury in 
neutral watery solution is readily soluble in a physiological saline 
solution. In the body this factor undoubtedly increases the solubility 
of not only albuminate of mercury, but of other organic compounds 
of the heavy metals. Sodium chloride is a constituent of every normal 
body fluid. 

"When a metal salt is brought into contact with an animal 
membrane, as an example the mucous membrane, the characteristic 
reaction with the formation of albuminate occurs. The reaction is 
more intensive at the surface of contact, and a layer of albuminate 
over the mucous membrane is the result. If this albuminate is not 
very soluble it forms a protective coating to the deeper structures. 
The film of albuminate forms a resisting membrane to the further 
penetration and absorption of substances in solution in contact with 
it. By far the most important constituent of this solution is the 
hydrogen salt of the acid ion set free when the albuminate formation 
occurs. If this acid be in itself a toxic and corrosive one, as in the case 
of mercuric chloride, then it will have its usual effect on the protoplasm. 
The film of protecting albuminate delays the diffusion of the hydro- 
chloric acid, hence modifies its corrosive action. If the acid ion of 
the metal salt be comparatively non-irritant or oxidizable, as in the 
case of lead acetate, then the influence of the salt as a whole will be 
astringent. 

In salts of this nature the concentration and solubility factors 
are of very great importance in the modification of the form of reac- 
tion of the tissues. Take, for example, mercuric chloride ; if the solu- 
tion is present in concentrated form, then the albuminate formed will 
be deeper, but the more concentrated acid ions liberated will penetrate 



FORMATION OF METAL ALBUMINATES 335 

deeper and quickly, notwithstanding the presence of the albuminate. 
Inflammation will, of course, be induced. The more dilute solutions, 
for example the 1 to 1000, do not ordinarily induce inflammation 
unless held in contact with the tissue for a long time, notwithstand- 
ing the formation of a surface layer of albuminate. It is obvious 
that the difference between a stimulative irritant and a corrosive 
action with such a salt as this is bounded almost wholly by the con- 
centration factor. The purgative salt, calomel or mercurous chloride, 
is a splendid example in this connection. Mercurous chloride is so 
slightly soluble in the alimentary canal that there are never at any 
one time sufficient ions present to produce more than a mild stimula- 
tive effect on the mucous membrane. Lead acetate is somewhat illus- 
trative of this variation in the action of metal salts, since the acetate 
is comparatively less irritant than the chloride of the mercuric 
salts. Although lead acetate is readily soluble, the acetic acid 
formed during its dissociation and reaction in the tissue is not so strong 
in its toxic effects on the protoplasm. Hence the albuminate coat 
modifies the action of the acetate down to the point where the total 
effect is only that of a pure astringent. But in this case a larger 
quantity of highly concentrated solution of lead acetate may become 
irritant or even corrosive in its action. Instances of acute gastritis 
are on record, illustrating this point. 

The salts of the organic compounds of the heavy metals, such as 
metal caseinate or soluble albuminate, are comparatively non-toxic. 
Although these salts are soluble, they ionize very slowly, if at all, and 
are, therefore, non-irritant. It is for this reason that the newer 
organic compounds of the heavy metals have been strongly recom- 
mended in order to displace the irritant and acute toxic action of the 
inorganic compounds. 

Speaking generally, the pure metals, as such, are inert. This, 
however, is only a comparative truth. One may take a piece of iron, 
a copper coin, or a drop of mercury into the mouth, or it may be 
swallowed and pass through the alimentary canal with comparatively 
no injury. However, the alimentary tissues and fluids do dissolve 
traces of metal, apparently with the direct formation of albuminates. 
This is held to be the case with metal mercury. If the mercury be 
in fine division, as, for example, in blue mass, enough of the metal 
may be taken up to produce a typical mercurial reaction. The 
presence of hydrochloric acid in the gastric juices may, and probably 
does, induce this reaction with certain metals. A state of fine divi- 
sion of the metal would favor this solution in hydrochloric acid. 



336 REACTIONS OF SALTS OF THE HEAVY METALS 

However, this point is based more on theoretical grounds than on the 
results of wide investigations. 

In recent years the metals have been recommended and used in 
practical therapeutics, as in the colloidal solutions. Colloidal metals 
are in a state of fine division, and in this form become available for 
the formation of albuminates and may, in fact in some instances do, 
enter the body quite rapidly, and produce the usual and typical 
reactions. 

2. The absorption of salts of the heavy metals. — Under the 
general heading of this division we may introduce the general under- 
lying principles which, with minor variations only, hold for practically 
all of the heavy metals. The basis for these observations has already 
been laid in the discussion of the general action of the heavy metals. 

Salts of the heavy metals are absorbed by the human body only 
through mucous membranes or from abraded surfaces, as, for ex- 
ample, wounds, ulcers, sores, etc. Absorption in any case is slow and 
occurs with difficulty. The very process of the formation of metal 
albuminates, as discussed above, for the time being delays or even 
stops the passage of those metals through any layer of living cells. 
In comparing different metals one can see at once that the rapidity 
of absorption in each instance will certainly depend upon the relative 
solubility of the albuminate formed. Since the albuminates are 
soluble in excess of protein, and that solubility is increased by the 
presence of salines, it is obvious that in the human body there are 
factors acting which are quite adequate to ultimately carry the 
metal into the circulation and thus distribute it throughout the 
body. The slowness of absorption is adequate to account for the fact 
that the heavy metals rarely produce acute general toxic symptoms. 
Not enough of the metal enters the system at one time to lead to the 
general reaction. Where apparent acute general toxicity occurs it is 
very apt to be complicated by the local reaction from the acute cor- 
rosion of a particular area, as, for example, in acute gastritis from the 
action of silver nitrate. 

Absorption takes place with fair rapidity from extensive abrasions 
or ulcers. The slow and long continued absorption will ultimately 
introduce enough metal of most heavy metals to lead to chronic 
toxic action. Perhaps the most typical example of this kind of metal 
poisoning is that of chronic lead poisoning. 

3. The distribution and excretion of the heavy metals in the 
body. — Under the action of the principles outlined in the preceding 
paragraphs, the salts of the heavy metals are introduced with more or 



DISTRIBUTION AXD EXCRETION OF THE HEAVY METALS 337 

less delay into the general circulation. In the majority of cases 
this absorption is extremely slow, and scarcely detectable traces are 
thrown in the circulation in any short period of time. Once in the 
blood, the metals are distributed throughout the body. They do 
not remain long in the blood; in fact, they are rapidly removed. 
Apparently they are taken up by the epithelial tissue of the vascular 
bed and passed over to the adjacent parenchyma of whatever organ 
they come in contact with. The liver is no doubt an important de- 
pository for heavy metals. Higher percentages of the metals are 
extracted from the liver than from any other organ of the body, but 
the metals are deposited in practically all organs, especially glandular 
organs and organs rich in connective tissue. 

The excretion of the metals takes place through all glandular 
structures. This includes not only the kidney, but the glands of the 
alimentary canal, and especially the alimentary mucosa. The mucosa 
of the large intestine has been proven to be a channel for the ex- 
cretion of a number of heavy metals, possibly because the important 
metal precipitant, hydrogen sulphide, is present in this tissue in greater 
quantity than in other portions of the digestive tract. The slow ex- 
cretion of the metals into the upper reaches of the alimentary tract 
brings about a condition favorable to their reabsorption. In fact, re- 
absorption occurs in greater or less degree with most all of the heavy 
metals. The net result is a cycle of reabsorption and reexcretion, oft 
repeated through a vicious circle which prolongs the general toxic 
action on the body tissues. It is this factor which so strikingly delays 
the final excretion of metals after their introduction into the body, a 
delay that is known to extend over several months. In the case of 
silver, the deposits in certain tissues, especially the subdermal con- 
nective tissues, become permanent, i.e., never dissolve. 1 

With these general factors in mind, we may take up the more im- 
portant individual metals of this series. The elements, iron, sulphur, 
and phosphorus, differ from the other heavy metals owing to the fact 
that these metals are present in normal protoplasm. They are, there- 
fore, singled out and treated first in the series. 

1 Dr. Crispin has just reported an interesting case of argyria from the 
use of collargol, Jour. Am. Med. Ass'n. Vol. LXIL, p. 1394, 1914. A laparotomy 
on this case revealed the interesting fact that the " tissues, muscles, and in- 
testines had a bluish tinge." It is of further interest that the treatment of 
the case for another affection by 10-grain doses of hexamethylamine led to 
a clearing of the skin and to partial disappearance of the argyria. 



CHAPTER XLVL 
IRON. 

The numerous iron salts known to chemists are not of pharmaco- 
logical interest as such. They for the most part ionize, in which 
process iron is set free as active cations. The physiological action of 
iron may be illustrated by consideration of ferric chloride. 

i. The normal relations of iron in the body. — The most typical 
iron-containing substance in the mammalian body is hemoglobin, 
present primarily in the red blood corpuscles, but also in smaller 
quantity in the muscles, certain glands, etc. Hemoglobin has the 
distinction also of being the most complex organic molecule of the 
mammalian body. It has the enormous atomic weight of 16,660. Iron 
is also yielded, though only in smaller quantities, by the muscles, 
liver, skeleton, in fact by most of the tissues of the body. It is 
present only in traces and possibly some portion of the iron attributed 
to certain tissues may have been derived from corpuscles of the 
blood still in the vessels of the organ, especially the iron of analytical 
chemical determination. The iron of skeletal muscle is attributed to 
a definite pigment muscle hemoglobin. "Whether this will hold for the 
iron of the liver is not so clear. 

Many conditions arise in the body in which there is great de- 
struction of the red blood cells with a corresponding loss of hemo- 
globin. This loss must be compensated for. In human diet the 
compensation is generally adequate through the iron content of the 
various materials of the food. In disease, for example in malaria, 
the iron may be so completely removed as to greatly weaken the indi- 
vidual concerned. In malaria the destruction of red blood corpuscles 
and the accompanying loss of hemoglobin may be so great as to lower 
the oxygen absorbing capacity of the blood for 50 to 70 per cent. 

Iron seems to be intimately bound up with general metabolism. 
If iron chloride is administered in small doses, a total of 10 to 30 
minims of the tincture of iron per day, it accelerates metabolism, 
acting very much as a mild tonic. However, the inorganic ferric 
chloride is metabolized with difficulty. In fact, it has been ques- 
tioned as to whether or not this compound can be utilized by the 

338 



IROX-PROTEIN COMPOUNDS 339 

body. It is certain, however, that the administration of the inor- 
ganic iron is favorable and one is compelled to assume that it is 
either directly utilized or that it acts as an iron sparer. By this 
latter view the ferric chloride would serve the purposes of iron 
excretion, thus conserving to the tissues for further metabolism such 
iron as would otherwise be excreted. 

2. Evidence of the absorption of iron. — A number of valuable 
experiments have been performed on mammals with the attempt to 
demonstrate the absorption of inorganic iron. If an animal be fed 
with an iron salt and after a sufficient time for absorption be killed and 
the alimentary canal be opened for its full length, and the mucous mem- 
brane painted with ammonium sulphide, it is found that two areas 
of the mucosa are blackened. The first one is in the upper portion 
of the small intestine, the duodenum; the second is in the lower 
portion of the colon and rectum. The experiments of Hall and 
others have given indication of the direct absorption of iron by the 
duodenum. It is not so clear whether the rectal iron is that being 
absorbed or iron on the way to excretion. Fistulas of the intestine 
have been established, and then iron fed on the assumption that any 
unabsorbed iron passing through the small intestine would be re- 
moved through the fistula without reaching the colon. Under these 
conditions iron is found in the content of the rectum, and it is as- 
sumed it reaches this point by excretion through the rectal mucosa. 

3. Iron-protein compounds. — Iron, especially in the form of 
chloride, acts as a precipitant of proteins. In the normal relations in 
the body the iron is present undoubtedly as an iron-protein, of 
which hemoglobin is the typical example. This has raised the ques- 
tion as to the form in which the iron is absorbed. It seems probable 
that it enters into a protein compound with substances of the food 
or of the mucosa and is absorbed into the body as such. 

Hall, by micro-chemical methods, has been able to demonstrate 
the presence of iron as such in the epithelium of the intestinal villi 
which he considers to be iron in process of absorption. 

Basing the procedure on the tendency of iron to form organic 
compounds, numerous organic iron compounds have been introduced 
into therapeutics in the hope that in this form the chemical will 
be more available to the body. Some of these preparations are less 
objectionable to the taste and less astringent in their influence on 
the mucous membrane, but on the whole they do not seem to favor- 
ably improve the protoplasmic reactions of the body more than do the 
inorganic compounds. 



340 IRON 

4. Astringent action. — Iron chlorides have for a long time been 
known to be markedly astringent to the mucous membranes of the 
body. "When taken by the mouth they have an acrid, " astringent " 
taste, and when swallowed in too large quantity lead to some reflex 
nausea and possibly vomiting. Owing to this local action there is a 
tendency to gastric inflammation. 

The local astringent action of iron has given the perchloride a 
reputation as a styptic in cases of local bleeding. The iron in this 
case has its usual chemical action of precipitating proteins, and thereby 
tends to hasten blood-clotting and the formation of a mechanical 
coat that obstructs the bleeding. It is effective in this regard both 
for external wounds and in bleeding from the nasal or buccal cavities, 
or in some deeper portion of the alimentary tract. However, the 
practical use of iron as a styptic is now more or less superseded by 
other agencies, for example preparations of epinephrine. 



CHAPTER XLVII. 
SULPHUR AND THE SULPHUR COMPOUNDS. 

In physiological chemistry we have already learned to know the 
importance of sulphur in the composition of protoplasm. All pro- 
tein bodies contain sulphur, along with nitrogen, oxygen, hydrogen, 
and carbon. Sulphur is present in various proteins in from 0.3 to 2.2 
per cent. Sulphur, therefore, is of an importance comparable to 
nitrogen in the reactions of protoplasm. The primary interest in the 
sulphur compounds is, therefore, physiological chemical. Among the 
questions of importance are the sources of sulphur and the forms in 
which it leaves the body through the excretions. The determination 
of the excretion of sulphur has come to be almost as important as 
the determination of nitrogen, in the light which it throws upon 
metabolic processes. 

The consideration of the detailed reactions of a normal nature 
will have to be left for discussion in connection with physiological 
chemical questions. We give here only a brief discussion of the be- 
havior of sulphur and sulphur compounds as such. 

i. Sulphur. — Sulphur in its pure form is a very inactive drug. 
If applied to the skin or when taken into the alimentary tract by way 
of the mouth it undergoes comparatively little change, and is thrown 
out of the body as sulphur in the stools. A certain amount is trans- 
formed into hydrogen sulphide in the intestinal tract. As sulphides 
this sulphur is absorbed and makes its appearance in the circulation 
to be excreted as sulphates in the urine, or to some extent as sulphides 
through respiration, where it gives a characteristic disagreeable odor 
to the breath. 

It is still an open question whether the display of neutral sulphur 
exerts any favorable action upon metabolism as such. Its presence 
in the alimentary tract acts as a mild cathartic, possibly contributing 
to the normal reactions of the bowel when this organ is relatively 
sluggish. 

2. Sulphides. — The sulphides are Bomewhat irritant and toxic. 
If introduced into the circulation they lead to depression of function 
of both the nerves and the muscular tissue; from the latter action 

341 



342 SULPHUR AND THE SULPHUR COMPOUNDS 

they weaken the circulation, and from the former produce some 
slight degree of narcosis. Harnack x has described a type of convul- 
sion in the frog following a toxic injection of hydrogen sulphide. 

It is probable that the small proportion of sulphides formed from 
neutral sulphur in the alimentary tract tends to produce this charac- 
teristic change in the important nervous and muscular mechanisms 
of the body. Traces of sulphide formed during intestinal digestion 
would be toxic to the extent of their concentration. 

3. Sulphates. — The oxidation of sulphur and sulphur compounds 
in the body is largely to the form of acid sulphur, the sulphates ; and 
to neutral sulphur, the various organic compounds. The sulphates 
are eliminated from the kidney as such. Their excretion is in acid 
form, hence any great increase in the quantity of sulphur excreted in 
this form tends to produce a degree of mild irritation of the renal 
tissue. This condition has been mentioned under the chapter on 
Saline Cathartics. 

4. The organic sulphur compounds. — A number of organic 
sulphurs are of some pharmacological interest. Of these may be 
mentioned sulphonal, which is mildly antiseptic, and ichthyol, which 
is a compound containing as much as 10 per cent, of sulphur, and 
has enjoyed some reputation as a mild antiseptic lotion. 

1 Harnack, Erich: Schmiedeberg's Arch., Vol. XXXIV., p. 156, 1894. 



CHAPTER XLVIII. 

PHOSPHORUS AND THE PHOSPHORUS COMPOUNDS. 

I. 
Historical. 

Phosphorus was first discovered by Brandt, in 1669, in the residue 
from the evaporation of urine. Tunnicliffe x states that it was a 
century later before phosphorus was shown to be present in the bones. 
Phosphorus plays a most important physiological role in the mam- 
malian body. It is a constituent of the most vitally necessary sub- 
stance of the nucleus, nucleo-protein, also of the phosphatids which 
serve so important a function in the process of nutrition of the 
young oviparous and ovoviviparous animals. Milk for the nourish- 
ment of the mammalian young also contains phosphorus in abun- 
dant quantities in the casein, and as salts of phosphorus. Here, 
as in the case of iron and sulphur, we find that the problem of the 
metabolism of phosphorus is of importance primarily to physio- 
logical chemistry. Still the influence of the substance on the body 
has both a toxicological and a pharmacological interest. 

Phosphorus is not tolerated by the body, except in combined 
form, i.e., as organic or as inorganic phosphates. If therapeutic 
quantities of free phosphorus be taken by way of the mouth, the 
substance is absorbed and slowly oxidized to the acid. The acid 
then forms salts with calcium, magnesium, or potassium. But very 
minute quantities are toxic. On the other hand, both inorganic and 
organic phosphates are constituents of every normal mixed food. The 
inorganic phosphates are constantly being excreted, chiefly through 
the urine. Phosphates are found to be necessary constituents of 
the food of both plants and animals. Plants are able to take up and 
utilize inorganic phosphates, deriving them from the soils and the 
soil waters. It is not so clear to what extent animals may utilize 
inorganic phosphates. That they do utilize organic phosphates has 
been clearly demonstrated, a point that will be discussed a little later. 

1 Tunnicliffe, F. W. : Archives internationales de Pharmacodynamic et de 
TMrapie, Vol. XVI., p. 207, 1906. 

343 



344 PHOSPHORUS AND THE PHOSPHORUS COMPOUNDS 

II. 

Outline of Pharmacological Action. 

1. Phosphorus is a general protoplasmic poison. 

2. It is characterized by excessive nitrogen elimination and by 
fatty degeneration. 

3. It interferes with specific functions, largely through derange- 
ment of general metabolism. 

4. Inorganic salts of phosphorus are non-toxic, but are available 
for the production of bone and stimulate bone growth. 

5. Organic phosphorus compounds are stimulative to general 
metabolic processes; they favor the utilization of nitrogen and the 
growth of muscular, glandular, and nervous tissues. 

III. 

Details of Pharmacological Action. 

i. Phosphorus as a general protoplasmic poison. — The element 
phosphorus is intensely toxic to animal tissues. This substance has 
been of interest for the last half century owing to the fact that it is a 
constituent of the preparation used in the manufacture of matches. 
Ordinary match heads contain from one to three milligrams of phos- 
phorus. Workers exposed to the phosphorus fumes and dust are 
subject to definite types of phosphorus poisoning. These present 
pictures of marked change in the calcareous structure of the bones, 
as well as of the teeth, produced by the absorbed phosphorus. They 
also are subjected to a condition of respiratory irritation affecting 
the mucous membrane down relatively deep into the lungs. Phos- 
phorus in this form is a vigorous irritant. If it be taken into the 
stomach the irritative change leads to an inflammatory condition 
of the mucosa, with accompanying griping pains, and generally with 
vomiting. 

All three of these lines of toxic influence show that uncombined 
phosphorus is poisonous to protoplasm. If the reaction throughout 
the body is followed, it is found that practically all tissues yield to 
its influence. The changes in the tissues are essentially of a patho- 
logical nature, beginning with absorption of water, cloudy swelling, 
disintegration, and ultimately fatty degeneration. According to 
Lusk, 1 the reaction is characterized by an increase in total metabo- 

1 Lusk, Graham: American Journal of Physiology, Vol. XIX., p. 461. 



PHOSPHORUS POISONING 345 

lism, as indicated by an increase in total nitrogen eliminated. There 
is also an excretion of lactic acid, which indicates interference with 
carbohydrate combustion. 

2. Fatty degeneration after phosphorus poisoning. — The ad- 
ministration of pure phosphorus has long been used to demonstrate 
the phenomenon of fatty degeneration. In the beginning the assump- 
tion was that phosphorus poisoning led to a breaking down of the 
protoplasm and to the formation, from its residue or during the 
process of its disintegration, of fat. In more recent years important 
and crucial tests have been made casting doubt upon the truth of 
this assumption. The question hinges on whether or not the observed 
disintegration of the proteins, which process is associated with an in- 
crease of nitrogenous wastes, leads to the formation of fats from the 
fatty or from the carbonaceous residues, thus accounting for the 
accumulation of visible fats in certain organs; or whether the fatty 
accumulations in phosphorus degeneration, so-called, are only trans- 
ferences of fat from other depots. Two methods have more recently 
proven fruitful in attacking the problem. Taylor 1 found that frogs, 
in which he produced fatty degeneration, contained less total 
fat than the normal controls. By the current theories, there should 
have been a gain rather than a loss of fat. Rosenfeld 2 attacked 
the problem from two angles. He demonstrated first that the 
increase of fat in the liver is associated with a decrease in the amount 
of fat in other fat depots of the body. His second point of attack 
hinges on the fact that the type of fat of each animal is characteristic. 
By feeding tallow, which is easily identified in comparison with dog 
fat, and at the same time producing phosphorus poisoning, Rosenfeld 
found that so-called fatty degenerated liver fat was composed of a 
high percentage of the foreign fat. Rosenfeld came to the conclu- 
sion that the fatty degenerations of this type are in reality fat trans- 
portations and do not arise in a breaking up or disintegration of 
the tissues. 

As a result of the tissue disintegration by phosphorus poisoning, 
there is a temporary increase in the formation of tissue enzymes, of 
which it is safe to assume lipase is one. An increase of the lipase 
sets up a series of interdependent physiological conditions, which 
quite adequately explain many of the cases of fatty accumulation in 
pathological degenerations, of which phosphorus poisoning is one. 

Taylor, A. E.: Journal of Eaperimental Medicine, Vol. IV., p. 300, 1800. 
2 Rosenfeld: Verhandlungen der deutschen pathologischen Gesellscliaft, Vol. 
VI., p. 71, 1904. 



346 



PHOSPHORUS AND THE PHOSPHORUS COMPOUNDS 



As Lusk has stated the case, " the sugar-hungry cells attract fat 
in greater quantity than they can burn," a statement that calls for 
a mechanism of lipase for the manipulation of the fats. 

3. The action on the skeletal structures. — The toxic action on 
the bony tissues was already mentioned. If phosphorus is given in 





A. 

Fig. 70. — Comparison of the humerus of a calf to show the influence of phosphorus 
feeding. A, section of the normal bone. B, after eight weeks of phosphorus feeding. 
There is little difference in the thickness of the shaft, hut a marked increase of the 
ossifications around the ends of the epiphyses. The spongy bone is greatly Increased 
and extends further into the shaft. From Wegner. 



sufficiently small doses through a considerable interval of time it 
produces a profound effect on the structural characteristics of bone. 
Phosphorus at first stimulates to bone formation. Evidently the 
activity of the osteoblasts is increased so that the laying down of 
bone, especially in young animals, takes place more rapidly than 
usual. In the long bones the denser portion of the shaft becomes 
relatively thicker, 1 and the cancelous tissue extends further down 
1 Wegner, Geo.: Virchow's Archiv fur Anatomie, Vol. LV., p. 11. 



THE RELATIONS OF THE INORGANIC PHOSPHATES 347 

the shaft, and the lamellae are thicker. The bone formation stimu- 
lated by phosphorus does not lead to a greater bone length. In the 
late and toxic stages of the administration there is a tendency to 
resorption of the bone salts, which finally weakens the bones and 
makes them more fragile. There are many points at present not 
fully explained as regards the toxic action of phosphorus, but ap- 
parently we are to look for the source in the interference with the 
metabolism of the bone-forming cells. 

4. The relations of the inorganic phosphates. — Aside from the 
toxic actions of pure phosphorus, the chief interest relates to the 
role and fate of its compounds in the body. Forbes x has recently 
reviewed this problem. He indicates that the organic compounds 
only are available for most of the tissues, but that the inorganic 
compounds can be utilized by such tissues as are particularly rich in 
this group of phosphates. The bones serve as the most typical example. 
Milk also contains a high percentage of inorganic phosphates. The 
usual salts are calcium, magnesium, iron, sodium, and potassium 
phosphates. The mineral bases form strong compounds, and are not 
readily displaced by the organic bases. On the other hand, organic 
phosphorus compounds contain a ready phosphorus supply, though 
an expensive one, for the inorganic uses of the body, especially where 
an adequate supply of mineral base is present (Forbes). 

With these principles in mind, it is evident that one of the most 
important influences of inorganic phosphates is that on bone metabo- 
lism. In the growth of bone the chief mineral constituent is calcium 
phosphate. If calcium and phosphate salts are not both present, 
then they must be supplied from their organic compounds or else mal- 
nutrition of bone results, i.e., osteomalacia, rickets, etc. 

Table showing the percentage of the constituents of the ash of the femur (Carnot). 



Man. 



Calcium phosphate. . . 87.45 

Magnesium phosphate 1.57 

Calcium fluoride .35 



Calcium chloride. . 
Calcium carhonate. 
Iron oxide 



.23 

10.15 

.10 



Ox. 



85.72 

1.53 

.45 

.30 

11.96 

1.13 



Inorganic phosphates serve two purposes, therefore they form a 
direct supply of mineral nutrients for inorganic phosphate purposes; 

1 Forbes, E. B. : Bulletin of the Ohio Agricultural Experiment Station, 
No. 201, p. 121, 1909. 



348 PHOSPHORUS AND THE PHOSPHORUS COMPOUNDS 

and they, as with inorganic iron, are phosphorus sparers. They 
conserve to the organism for the more complex reactions the higher 
compounds of the lecithins, nucleo-protein, etc. Forbes, feeding pigs 
with different phosphorus compounds in the supplement ration, found 
that raw bone meal and bone flour ' ' increased the density, the volume, 
and the ash per cubic centimeter of volume, of the bones." There 
was no obvious advantage in muscular development. 

In the Rocky Mountain and western region of the United States, 
where alfalfa forms the winter ration for the great sheep flocks, it 
has been noted that the young lambs in utero grow such large skele- 
tons that many are killed at birth. 1 Alfalfa has the largest mineral 
content of the vegetable feeds. It is particularly rich in calcium, 
potassium, and phosphorus, as well as in protein. The phosphorus 
stimulates to greater bone growth, especially in the presence of an 
abundance of mineral bases, of which calcium is of the chief impor- 
tance in this instance. A favorable combination in the feeds of 
protein with the saline substances produces in addition to the skeletal 
growth an unusual mass development of the soft tissues. 

5. Organic phosphorus compounds. — It is well established that 
organic phosphorus compounds are necessary for the growth and 
activities of all the tissues of the animal body. Deficiency in this 
element in organic form leads quickly to malnutrition, and in ex- 
treme cases malformation. The most abundant organic phosphates 
in the foods are: (1) phosphatids, the lecithins; (2) phospho-proteins, 
of which the casein of milk is an example; and (3), the nucleo-pro- 
teins, always present in the cell nuclei as compounds of nucleinic 
acid. Eepresentatives of these classes of organic phosphates are all 
available, both for the organic and the inorganic phosphorus supply. 

The brain is especially rich in phosphorus, 3.7 to 4 per cent, and 
more, chiefly present in the glycero-phosphoric acid of the brain leci- 
thins. It is to be expected that interference with brain metabolism will 
occur if there is a dearth of organic phosphorus in the food supply. 
Under these circumstances one cannot escape the inference that 
phosphorus compounds are very vital to the reactions of the brain, 
including those processes in which conscious thought have their 
physiological foundations. 

Organic phosphorus stimulates growth. Tuniii cliff e found that the 
addition of the phosphorus of a casein and a sodium glycerophosphate 
preparation to the diet of two children was followed by an increase 

1 Unpublished results used by permission of President H. J. Waters of the 
Kansas State Agricultural College. 



ORGANIC PHOSPHORUS COMPOUNDS 349 

in the amount of phosphorus assimilated and retained in the body. 
There was also an increase in the amount of the food nitrogen, 
assimilated, a fact that had been previously demonstrated. It is 
this favorable stimulation of metabolism that has given lecithins 
and the caseins such a strong position among the food drugs. 

The nucleo-proteins are also stimulative, but not to a favorable 
increase in constructive metabolism. The nucleins lead to a leucocy- 
tosis, or increase in the number of white blood cells. This is fol- 
lowed by a rise of the amount of phosphorus excreted greater than 
can be accounted for by the nuclein phosphorus given. 



CHAPTER XLIX. 

ARSENIC AND ANTIMONY. 

A. ARSENIC. 

I. 

Introductory and Historical. 

The pharmacological importance of arsenic received a new im- 
petus when Ehrlich introduced synthetic compounds of arsenic as 
specific poisons for certain infectious organisms. The element arsenic 
is non-toxic as such. The metal is non-soluble in water, therefore 
cannot be absorbed from the alimentary canal. Arsenic compounds, 
especially the trioxide, the arsenites, and the sulphites, are peculiarly 
toxic to all forms of living matter. This toxicity has been known 
for many centuries. At the present time arsenic is used extensively 
in the arts. This gives opportunity for accidental poisoning. For 
example, Paris green, which is an arsenite of copper, and arsenate 
of lead are the chief insecticides used in vegetable and fruit garden- 
ing. Where such vegetables or fruits are carelessly prepared for 
food opportunity is given for arsenic poisoning. Arsenic is also 
present as an impurity in certain of the chemicals used commer- 
cially, for example sulphuric acid, a fact which gives secondary 
opportunity for arsenic poisoning. 

The compounds of special interest are arsenious acid and its oxida- 
tion product, arsenic acid. Of the numerous synthetic arsenic com- 
pounds which have been introduced into medicine the more impor- 
tant are atoxyl, or sodium arsanilate, C 6 H 4 (NH 2 ).(AsO.OH.ONa) + 
3H 2 0; cacodylic acid, (CH 3 ) 2 AsO.OH, and salvarsan, or arseno- 
benzol, HCLNH 2 .OH.C 6 H 3 As :As.C 6 H 3 .OH.NH 2 .HCl+2H 2 0. 



CH 3 / AS \OH 



/OH 

O = As— OH 

\OH 

Arsenic acid Dicacodylic acid 

As 

/\ 
HC1.NH 3 I | NH 2 .H» 

OH OH 

Arseno-benzol 
350 



OUTLINE OF PHARMACOLOGICAL ACTION 351 

II. 

Outline of Pharmacological Action. 

Arsenic compounds interfere with metabolism, hence 

1. Arsenic is a general protoplasmic poisoning. 

2. The systemic effects are largely secondary to toxic derange- 
ment. 

3. In minute quantities arsenic is stimulative to growth. 

III. 
Details of Pharmacological Action. 

i. General toxicity of arsenic compounds. — Arsenic acid is one 
of the most toxic of the forms in which arsenic is administered to 
the body, and it will serve as a type for the discussion of further 
details. Arsenic poisoning leads to a chain of obscure symptoms 
which have their expression through the perverted functions inci- 
dent to general toxic action on the tissue protoplasm. For example, 
arsenic acid, which is dissolved with difficulty and ionizes slowly, 
leads to a slow poisoning of the cellular protoplasm. The toxic 
symptoms come on so slowly and are so obscure that diagnosis is 
difficult. Even in the acute cases this statement holds. The effects 
last for long periods, and chronic arsenic poisoning persists for 
weeks after the cessation of the drug. Where arsenic is used as a 
cosmetic and the administration oft repeated, pronounced chronic 
effects may arise and be far advanced before they are identified. 

The phenomenon of arsenic poisoning may be divided into stages, 
of which the first consists only of general weakness associated with 
derangement of nutrition. The person does not desire food and the 
food that is taken is imperfectly digested, and there may be a marked 
disturbance of the alimentary canal accompanied by diarrhea. 

A little later, when the arsenic has acted more generally through- 
out the body, there is swelling of the mucous surfaces, including the 
membranes of the respiratory tract, of the alimentary tract, and the 
uro-genital system. 

The epidermis is also markedly affected. Sometimes actual disin- 
tegration takes place. Uusually there is an increase in pigmentation, 
and the skin becomes noticeably darker. In this stage arsenic is to 
be found in the skin and skin appendages, and it can be easily identi- 
fied chemically from the hair. 

In the later final stages of chronic poisoning there is paralysis 



352 ARSENIC AND ANTIMONY 

of the neuromuscular mechanisms. There is also a disturbance of 
the sensory side of the nervous system. Inflammation occurs, whereby 
the ordinary normal physiological sensory responses are greatly ex- 
aggerated. There is a tingling and stinging sensation in the skin, 
especially in the extremities. 

Localized areas often give rise to acute pains. The muscular 
disturbances are associated with paralysis of the motor nerves, in 
which case the muscles themselves tend to degenerate. General in- 
coordination of locomotor activity is, therefore, characteristic of the 
late chronic stage. 

2. Action of arsenic on the circulatory system. — While arsenic 
must be classed as a general poison, its influence on the circulatory 
system creates a pronounced secondary effect on other portions of the. 
body. In the early chronic stage of arsenic poisoning there is a 
certain degree of edema. This can best be explained on the assump- 
tion that the endothelial linings are directly affected by arsenic to 
such an extent as to interfere with their normal resistance. While 
the extremely minute dose may stimulate endothelial activity, the 
toxic reactions lead to degeneration. There is, therefore, a loss of 
tone in the smaller blood-vessels, especially of the capillaries, with a 
corresponding dilation. 

Arsenic acid is toxic to the heart. If isolated hearts, either of 
the lower vertebrates or of mammals, be perfused with a solution 
containing this drug, both the rate of contractions and the amplitudes 
are diminished. Only a very small margin of drug concentration 
exists between that strength which will reduce the rate of the heart 
and that which will completely eliminate its rhythm. The heart 
will recover readily from a short period of action, but prolonged 
contact with the arsenic is severely toxic. The action is primarily 
on the cardiac muscle. 

3. The action of arsenic on the alimentary tract. — The acute 
toxic action of arsenic on the alimentary tract produces a vigorous en- 
teritis. The symptoms appear early. The mucous membrane of the 
stomach shows the usual inflammatory condition with redness and con- 
gestion. The process is slower than with the ordinary corrosives, yet 
there is undoubted degeneration of the lining epithelium, accom- 
panied by the usual change in resistance. The inflammation may take 
the form of a violent enough gastritis. The reflexes then produce 
vomiting, marked increase in the secretions, and often an increase in 
the intestinal peristalsis. Where the action is intense there is also 
a fall of blood-pressure with symptoms of shock. 






ARSENIC ON METABOLISM 353 

On the intestine arsenic leads to a paralysis of the capillaries 
with corresponding congestion. A reduction of epithelial resistance 
occurs, thereby increasing the loss of fluids from the epithelium into 
the cavity of the canal. If the corrosion is intense and prolonged, 
then there may be shedding of the epithelium. This adds to the 
exudates, and in association with the increase in peristalsis contributes 
to the so-called " rice water " stools, which are characteristic of this 
form of poisoning. The local action along the alimentary canal is so 
acute that the whole process often becomes decidedly violent. If so, 
the final death may come on rapidly because of extreme exhaustion. 

In the milder arsenic toxication the action on the alimentary 
mucous membrane is less intense. There often is a slow chronic 
degeneration of these cells associated with similar degenerative stages 
in other parts of the body. The condition comes on so gradually 
that the acute phenomena just described are passed over and the 
opposite state of a sluggish and inert canal, i.e., a condition of gen- 
eral constipation, may be the prominent picture. 

4. Arsenic on metabolism. — "With arsenic compounds, as with 
the phosphorus compounds, minute doses are at first beneficial in 
their influence on protoplasm. For example, there is an increase in 
the growth of the epidermal structures, a laying down of fat in the 
subdermal adipose tissues, and apparently a favorable reaction on 
the neuro-muscular tissues. This influence, as also in the case of 
phosphorus, quickly passes into the toxic injurious stage. In the 
toxic stage practically all the tissues undergo degeneration in some 
degree. The typical pathological picture induced is one of an 
initial cloudy swelling, followed either by inflammation or by rapid 
disintegration. In the nervous tissues these stages first produce a 
hypersensitiveness, then later paralysis. In the glandular tissues 
there is an increase of secretion followed by degeneration and loss 
of secretory power. In the alimentary canal the phenomena have 
already been given above. In the liver, however, there is at first an 
increase in the formation of bile, but later a marked degeneration 
of the parenchyma. In the skin the increased growth is followed by 
pigmentation and then by degeneration, and in the kidney a mild 
nephritis, followed by degeneration with suppression of the urine. 

5. The excretion of arsenic. — Arsenic is excreted in practically 
all of the secretions of the body, particularly in the secretions of the 
skin, namely, the sweat and milk, and of the kidney. Some arsenic 
is lost by way of the alimentary canal, but most of it is thrown off 
through the urine. Arsenic is only slowly excreted. Following a 



354 ARSENIC AND ANTIMONY 

single dose the process of excretion may last through ten or twelve 
days. In fact, it has been observed in the urine as high as 160 days 
after the last administration. Evidently the drug, is stored in the 
different organs of the body in a form from which it is only slowly 
liberated and finally thrown off. 

IV. 

Organic and Synthetic Arsenic Compounds. 

Eeference was made in the introduction to the work of Bhrlich 
in deriving the synthetic arsenic compound salvarsan. The general 
toxicity of arsenic led Ehrlich to the special attempt to build up 
arsenic compounds of reduced toxicity to .the tissues of the host 
while retaining the usual toxic action for invading organisms. Ehr- 
lich 's ambition was to secure a selective antisepsis by this means. 
The organic arsenic compounds, namely, cacodylic acid and arsanilic 
acid, have long been known to possess a high degree of toxicity for 
certain pathogenic germs. Ehrlich developed a series of instructive 
and valuable synthetic products by the attachment of arsenic to vari- 
ous derivatives of the benzine ring compounds. 

6. The arsanilates. — Arsanilic acid is a compound produced from 
arsenic acid, in which anilin takes the place of one hydroxyl. Various 
metallic salts are derived from arsanilic acid, producing arsanilates 
that have been introduced into New and Non-official Remedies under 
special names, usually proprietary. Sodium arsanilate (atoxyl), 
C 6 H 4 (NH 2 ).(AsO.OH.ONa)+3H 2 0, is described by the 1914 edition 
of New and Non-official Remedies in the following terms: " The 
arsenic of the arsanilic acid is liberated very slowly in the system, 
thus producing the ordinary therapeutic effects of arsenic, with a more 
continuous and less toxic action and less irritation. Toxic effects 
from excessive doses have been frequently noted, although the toxicity 
of sodium arsanilate is stated to be about 1-40 of that of arsenic 
trioxide. The poisonous effects appear to be due largely to the arsenic 
component, the aniline taking no part in them. It is claimed that the 
use of sodium arsanilate is not followed by irritation, abscess forma- 
tion, etc., which sometimes follow the use of other preparations of 
arsenic. The use of sodium arsanilate in large doses has occasionally 
been followed by degeneration of the optic nerve, leading to blindness. 

" Sodium arsanilate has been recommended for the conditions 
which are favorably influenced by arsenic, such as anemia, nervous con- 
ditions, and diseases of the skin. It is said to have been very success- 



ORGANIC AND SYNTHETIC ARSENIC COMPOUNDS 355 

ful as a remedy for trypano-somiasis, both of animals and of man, and 
is also said to be useful in other protozoal diseases, such as syphilis, 
malaria, and kala-azar. " 

The importance of this anilin arsenic compound is in association 
with its toxicity for the infectious organisms, such as in syphilis, 
malaria, etc. In the body the compounds break up, liberating arsenic 
in such form as to be specifically toxic for the invading organism, 
It was at first thought that this compound was not toxic for the body 
tissues, but numerous cases have arisen leading to disintegration and 
loss of function of special structures, the most distressing of which is 
that of blindness from degeneration of the optic nerve. 

7. Salvarsan. — At this point may be discussed the synthetic work 
of Ehrlich in the building up of compounds with a maximum of 
toxicity to invading organisms, associated with a minimum of toxicity 
for the tissues of the host. Ehrlich has exhaustively considered this 
question on theoretical grounds. His views led him to construct numer- 
ous synthetic compounds, some of which he has shown to be practically 
selective in their toxicity for invading organisms. In 1910 the medical 
world was electrified by the announcement of a compound, number 
606 of his series, which was specifically toxic for the spirillum of 
syphilis. This compound is arseno-benzol, or salvarsan. It presum- 
ably owes its action to the special form in which the arsenic is car- 
ried. 

The serum studies which have led to the development of special 
means of detecting invading organisms have given practical diagnos- 
tic signs for many of our most dreaded diseases, the Wiedal reaction 
for typhoid, the tuberculin reaction for tuberculosis, and the "Wasser- 
mann reaction for syphilis. By the application of the specific syphi- 
litic test it is now possible to determine positively whether or not the 
body of a given individual has been invaded by this dreaded organ- 
ism. The arsenic treatment, through the specific salvarsan, is borne 
especially well by the body in which the spirillum is present. Some 
condition developed by the spirillum seems to make the body toler- 
ant of the arsenic compounds in this form. This tolerance is greater 
than that possessed by the normal body, hence in practical treatment 
the safe method is first to determine the presence of the organism 
by the Wassermann reaction and then give the specific salvarsan in 
the belief that the tissues will resist the toxic substance and the in- 
vading organism will succumb without danger to the host. 

Ehrlich has announced the almost unbelievable result that after 
single injections of salvarsan the invading organisms completely dis- 



356 ARSENIC AND ANTIMONY 

appear. Numerous clinical treatments in Europe and in America 
have abundantly established the specific value of this agency along 
clinical lines. 

B. ANTIMONY. 

Antimony, which is the chemical relative of arsenic, has also been 
used in medicine for many years. Like arsenic, antimony is gen- 
erally toxic and more or less irritant to the tissue cells. The form 
used in medicine is tartrate of antimony or tartar emetic. 

i. The irritant action of antimony. — Antimony is far more di- 
rectly irritant than arsenic, and therefore can be used externally as 
a skin irritant and internally as a strong gastric irritant. It is 
this last factor which has given to the compound the name of tartar 
emetic. The application of antimony to the skin leads to local in- 
flammation. Around the mouths of the sweat glands and the sebaceous 
glands, where the drug is absorbed more deeply, it tends to produce 
pustules. This reaction produces stimulations of the nerve endings, 
reflexes which are discussed more fully under the head of Counter 
Irritants. 

Antimony given internally in relatively small doses, 30 mgr., 
produces at once an acute irritation of the lining of the stomach. 
This irritation also leads to vigorous nerve reflexes. The result is 
an increase of the secretions, both salivary and gastric, in the milder 
stages of its actions, and nausea and vomiting in the more intense 
stages. This function of inducing vomiting is the one that has been 
most used in therapeutics. 

Antimony is not so readily absorbed as some drugs, unless by 
mischance there be gastric ulcer or other form of abraded surface. 
The systemic effects of antimony are toxic, somewhat comparable to 
arsenic in this regard. There is, therefore, danger of nervous, of 
vascular, and other disturbance of vital functions, such as occasionally 
lead to severe and dangerous collapse. 

Antimony is primarily excreted with the feces, but it is present 
in traces in the secretions. The antidote is tannic acid, which forms 
an insoluble precipitate, in which form it can be removed from 
the stomach by the usual methods of lavage. 



CHAPTER L. 
LEAD SALTS. 

I. 

Historical and Chemical. 

Lead is a toxic metal, the salts of which vary in virulence very 
largely in proportion to their solubility in water and in the body 
fluids. The salts of especial interest are the insoluble salts, such as 
litharge, or lead monoxide, PbO, sulphate PbS0 4 carbonate, or white 
lead, PbC0 3 , and the iodide, Pbl 2 . The important soluble salts of 
lead are the nitrate, Pb(N0 3 ) 2 , and the acetate, Pb(C 2 H 3 2 ) 2 , or sugar 
of lead, is the most soluble of all, and is the salt most used in prac- 
tical therapeutics. Lead salts are of chief pharmacological interest 
because of the great intensity of their toxic action, rather than be- 
cause of their value in therapeutic practice. 

II. 

Outline of Pharmacological Action. 

The reactions of lead in the body may be summarized as follows : 

1. General toxicity to protoplasm because of the formation of 
lead protein compounds after absorption. 

2. A cluir act eristic astringent action of the dilute salts. 

3. Concentrated lead salts are irritative, and hence produce local 
inflammation. 

4. There is a strong tendency to chronic irritation after prolonged 
absorption of minute quantities. 

III. 

Details of Pharmacological Action. 

i. The general toxic action of lead salts. — Lead salts owe their 
toxicity primarily to the fact that they precipitate proteins. The 
formation of lead protein compounds in the protoplasm of the cells 
destroys the normal power of physiological reaction of the tissues 

357 



358 LEAD SALTS 

concerned. This statement holds whether the action be on free 
mucous surfaces or on abrasions, as in the use of lead salts as astrin- 
gents. The reactions are the same when the salts have entered the 
circulation and reached the tissues by the paths of general distribu- 
tion. The toxic picture, as expressed through changes in the coordi- 
nations throughout the body, varies, therefore, according to the degree 
of poisoning on one or the other tissue, as the case may be. 

The insoluble salts are not absorbed unless they be converted while 
in contact with the moist tissues into soluble forms, as happens 
typically with the lead carbonates. Most soluble lead salts, like 
salts of mercury, penetrate the tissues comparatively rapidly. When 
a solution of a salt of lead is taken into the stomach, it begins at once 
to diffuse through the mucous membrane.- However, it quickly 
forms a superficial layer of insoluble lead protein; in other words, 
produces a tanning effect on the surface layers of the mucosa. In 
consequence of this initial action the further absorption of lead is 
delayed, though not prevented. The intensity of the local action of 
lead depends largely on the concentration of the solution. If the dilu- 
tion is great, then there will be only a local astringent action. If 
the concentration is medium, the astringent action will pass over into 
a definite irritation that will involve the sensory nerve endings, 
which will in turn lead to reflex changes in secretion, peristalsis, etc. 
The solutions of greater concentration lead to an immediate irrita- 
tive process and acute toxic action, which produces nausea and 
vomiting, and ends in acute inflammation. 

"When the lead salts reach the intestines the cycle of changes 
which have been described for the stomach are repeated. The more 
rapid absorption from the intestinal region induces a greater intensity 
of local action. This local action affects the vascular channels, pro- 
ducing a stricture of the blood-vessels, which takes the character of a 
vascular spasm, therefore producing an asphyxial condition of the 
tissues of the regions supplied. The direct lead action on the smooth 
muscle of the intestinal walls produces prolonged contractions, with 
the griping pains which characterize the so-called lead colic. 

In acute lead poisoning, this cycle of symptoms may occur within 
a very short period, i.e., within a few hours. Systemic effects not 
mentioned but associated with acute lead poisoning are great thirst, 
nervous distress, and prostration, sluggish circulation, with cold ex- 
tremities. In the later periods of the cycle a suppression of the urine 
sometimes occurs, and there are general muscular cramps, which may 
end fatally in convulsions or in paralysis. As a rule, however, this 



CHRONIC LEAD POISONING 359 

extreme acute toxicity does not occur, and the victim may slowly 
recover even after large doses of sugar of lead, the most soluble of 
the lead salts. 

The obvious antidote for acute lead poisoning is administra- 
tion of an indifferent sulphate or carbonate, such as sodium sulphate 
or carbonate, with the hope that the soluble lead may be converted 
into an insoluble salt, and in that inert form be eliminated from the 
body. 

2. Chronic lead poisoning. — Acute lead poisoning, as described 
above, is rare as compared with the number of cases of chronic lead 
poisoning. Lead in one form or another is used very extensively 
in the arts, and, as may be expected, chronic lead poisoning, there- 
fore, is commonly found among painters, lead workers, plumbers, 
glass workers, and pottery glaziers. Lead may enter the body by 
inhalation from the dust, may be absorbed through skin abrasions, 
but it is more commonly taken up by slow and continual absorption 
from the alimentary canal after entrance by way of the mouth. 
Drinking water may contain lead from lead pipes, foods also preserved 
in lead sealed containers may be the source of lead intoxication, but 
uncleanliness in handling lead-containing substances is the usual 
source of intoxication. 

The slow and continual absorption of lead gradually introduced 
into the general circulation and distributed throughout the body 
is the most common history of lead poisoning. The reaction with 
protein renders it difficult of excretion, therefore there is a gradual 
and accumulative action. The acute or local symptoms may be 
entirely absent, but in due time general toxic symptoms make their 
appearance. The more common introductory symptom is acute in- 
testinal cramps, i.e., " lead colic." This is followed, after a few days 
or weeks, often without other premonitory warning, with muscular 
paralysis. It is an interesting observation that the paralysis most 
always affects the nerves of the upper extremities, beginning at the 
points of distribution of the nerves to the muscles of the fingers, 
hand, and arm. Muscular control is lost in a definite order. The 
first affected are the extensors of the middle fingers, then of the 
thumb and little finger, and then gradually of the wrist, leading to 
the characteristic " wrist drop." The attack is usually, but not al- 
ways, bilateral, and gradually extends to other muscles. The fuller 
details of this condition may be had from more extensive works on 
toxicology. Other nerve symptoms are due to the loss of sensory 
functions. 



360 LEAD SALTS 

The organs of excretion, especially the kidney, and to less extent 
the salivary and other glands of the alimentary tract, are strongly 
affected in chronic lead poisoning. Early nephritis occurs, followed 
by marked degeneration and necrosis of the nephridial tubules. 

3. The action of lead on the digestive tract. — Under the head- 
ing of the toxic action of lead we have already discussed some of the 
changes produced on the alimentary tract. However, further em- 
phasis should be given to the fact that the gastric and intestinal 
symptoms represent a complex, not only due to local action, but to 
special action after absorption. For example, the intravenous injection 
of lead salts produces diarrhea, and the characteristic lead colic. 
Diarrhea from this method of treatment is accompanied by violent 
intestinal muscular spasms. The muscular walls do not completely 
relax, but persist in clonic contraction. In fact, in the chronic stage 
the intestinal spasm loses more and more its peristaltic character, 
and hence constipation becomes a constant and persistent symptom 
from the peculiar type of interference with the normal movements 
of the intestinal tube. 

It is not fully clear whether the intestinal spasms are due to the 
direct stimulation of the smooth muscle, as such, or to primary action 
of the lead on the local nervous mechanism. If one may draw conclu- 
sions from evidences of the toxic nature of the lead reactions in other 
parts of the body, he would infer that the nerve explanation was 
the more probable. During the muscular spasm of the intestine 
there is also a marked spasm of the blood-vessels, which produces a 
local asphyxiation contributory to the general toxicity. 

4. Excretion of lead by the salivary and intestinal glands. — 
Lead is excreted to a slight extent by the salivary glands. It is 
present in the saliva and the mouth in quantity sufficient to produce 
the characteristic blue line along the teeth near the margin of the 
gums. The insoluble lead sulphide is formed and deposited at this 
region, especially if any uncleanliness of the teeth exists. 

The glands of the stomach and of the intestines also excrete lead 
salts. In fact, the mucosa itself possesses this function, accounting, in 
part, for the final loss of lead through this channel. But in this 
instance, as in the case of morohine, there is a considerable reabsorp- 
tion of the lead, which establishes a vicious circle. This fact con- 
tributes to the difficulties with which lead is finally and entirely ex- 
creted from the body. 

5. Excretion of lead by the kidney. — The major portion of the 
lead is slowly excreted by the kidney. It is the excretion by this organ 



THE REACTIOX OF LEAD OX THE NERVOUS SYSTEM 361 

that brings the toxic metal in intimate contact with the nephridial 
epithelium, hence the result is more or less disastrous. The situa- 
tion is very similar to that of the excretion of the salts of mercury. 
There is a tendency toward protoplasmic precipitation, which 
leads to acute inflammation or nephritis, and this is followed by 
parenchymatous necrosis. Profound functional disturbance is in- 
evitable. A voluminous urine of low specific gravity characterizes 
the early stages of the disease, uremia and dropsy the later chronic 
stages. 

6. The reaction of lead on the circulatory system. — After the 
absorption of lead into the blood stream it tends to react both with 
the constituents of the blood and with the lining epithelium of the 
blood-vessels. As a result of the former reaction there is some change 
in the character of the blood plasma. It is true that this leads to 
only secondary stages in lead poisoning. The chief damage to the 
blood falls upon the white corpuscles and the erythrocytes. The 
white corpuscles lose their ameboid character, become sluggish, and 
tend to disintegrate, hence their activities are reduced below the 
normal. Disintegration of the red corpuscles, with a tendency toward 
the formation of methemoglobin, has been described. This process 
leads to a reduction of the percentage amount of respiratory pigment, 
and there follows the chain of symptoms expressed by anemia and 
malnutrition. The reaction of lead salts on the epithelium of the 
blood-vessels produces a toxic condition which, when prolonged, 
leads to two unfavorable symptoms. The first of these, which arises 
early, is characterized by a tendency to contraction or spasms of the 
arterioles and capillaries. The second and later symptom is charac- 
terized by developing arterio-sclerosis, with the secondary accompany- 
ing symptoms, which that term implies. 

Various interferences with the normal rhythm and force of the 
heart's contraction have been ascribed to the effect of lead salts. How- 
ever, lead only slowly combines with striated muscle substance, of 
which cardiac muscle is a type. After prolonged action there is a 
tendency to muscular weakness and cardiac paralysis, quite com- 
parable to the chronic changes in skeletal muscle. 

7. The reaction of lead on the nervous system. — Harnack * also 
made a study of the influence of lead on the nervous system of frogs 
and mammals. It is to his classical work that we owe our experi- 
mental conception of this field. He found that lead salts after ab- 

1 Harnack, E.: Archiv fiir experiment elle Pathologie und Pharmakologie, 
Vol. IV., p. 152, 1878. 



362 LEAD SALTS 

sorption produced strong initial stimulating effects on certain cen- 
ters of the nervous system. These facts were demonstrated through 
the muscular responses given by dogs. In determining the action on 
the blood vascular system it was found that lead salts injected 
into the circulation after section of the cervical sympathetic nerve 
on one side produced general blood vascular spasms. The contrac- 
tions were stronger on the unoperated side, showing that lead stimu- 
lated the vasomotor center as well as the smooth muscles of the ves- 
sels. In the later or chronic action of lead, this nervous reaction 
becomes toxic, producing paralysis of certain nerve centers. The 
paralysis is not specific and varies much in different individuals. It 
is this toxic effect on the cortical areas which constitutes the en- 
cephalopathia saturnalis. As a result of the cortical disturbance 
there is a marked interference with the psychic factors as expressed 
by restlessness, occasional delirium, usually followed in the end by 
marked depression and central paralysis. 

In closing the discussion, one may emphasize the fact that sec- 
ondary physiological effects of lead poisoning produce variations in 
the primary symptoms. The uremic convulsions, which follow the 
destruction of the renal function, will suffice as a single example of 
such secondary results. 

The peripheral nerves are poisoned in the later stages of lead 
action. In fact, the most typical phenomenon of lead poisoning, 
namely wrist-drop, is due to paralysis of the motor nerves rather 
than of the muscles concerned. The action is not directly upon 
the motor nerve ending, but upon the axis cylinders along the course 
of the nerves. 

8. Muscular effect of lead poisoning. — Harnack's classical pic- 
ture of the effects of lead on striated and other muscles shows a 
marked interference with the typical muscular contraction and the 
expenditure of muscular energy. His diagrams indicate a very char- 
acteristic onset of fatigue with a minimum of recuperative power, 
also a typical arrest of the relaxation phase at the last third. This 
change in a way resembles that which characterizes veratrine, but 
it does not come so early in the relaxation. 

This phenomenon was observed in the muscles of frogs and rab- 
bits, and it involved the striated skeletal and cardiac muscles. As 
the lead action proceeded the muscle substance lost its irritability 
and finally became paralyzed, or at least unresponsive. Strange to 
say, the muscles of the dog were, in Harnack's hands, quite immune 
from these typical changes. 



MUSCULAR EFFECT OF LEAD POISONING 363 

That there are additional factors involved has been shown by 
Cash. 1 Cash studied lead muscular poisoning under the influence 
of variations in temperature. At temperatures of from 15.5° to 17° C. 
the muscles did not give the characteristic lead contractions. At 
temperatures of 30° C. and more the lead poisoned muscles did give 
this result. Cash came to the conclusion that for some unknown 
reason the combination of lead with the muscular substance is pre- 
vented by certain unfavorable temperatures and favored by others. 

Cardiac muscle seems to fall into the same class as skeletal 
muscle, so far as lead action is concerned. We find the heart, there- 
fore, contracting more feebly and at a slower rate, and with a ten- 
dency to prolonged diastole. However, the heart responds to its 
nerves so long as its muscle remains sensitive to direct stimulation. 

Smooth muscle also is changed by the formation of lead proteins in 
its protoplasm. This is indicated by Harnack's experiment quoted 
above on the circulation in the ear of the rabbit after the section 
of the vasomotor nerves. The contraction of the blood-vessels on 
the isolated side can only be explained as a direct muscular effect. 
This view is strengthened by the actions on the alimentary canal, 
which have been discussed above. 

1 Cash, Th.: "Archiv fur Experimentelle Pathologie und Pharmakologie," 
Supplementband, Schmiedeberg's Festschrift, p. 93, 1908. 



CHAPTER LI. 
ZINC SALTS. 

I. 

Details of Pharmacological Action. 

The zinc salts, that are of interest in a pharmacological way, are 
the oxide ZnO, the sulphate ZnS0 4 and the chloride ZnCl 2 . The oxide 
is insoluble, while the sulphate and chloride are very soluble, therefore 
the more readily absorbed by the mucous membrane of the alimentary 
canal. 

i. General toxic and disinfectant action of zinc salts. — The salts 
of zinc precipitate proteins as in the case of the lead salts. The 
formation of insoluble albuminates on protoplasmic surfaces gives 
to the zinc salts their characteristic astringent property. Zinc 
albuminates are even less soluble than lead albuminates. When the 
action is more intense, as in the more concentrated solutions of zinc, 
the effect on protoplasm is merely irritant. Zinc chloride being more 
soluble, therefore penetrates more readily into the tissues, hence it 
is the more irritant of the zinc series. The chemical action of zinc on 
protoplasm gives to its salts their antiseptic property. Zinc chloride 
enters into the composition of special disinfectant solutions such as 
in Pott's solution. 

2. The local action of zinc salts. — In the human body the local 
application of zinc salts produces its effects according to the surface 
involved. The skin is non-absorbent, therefore zinc salts have little 
or no influence. The more soluble and stronger salts, as for instance 
zinc chloride, will produce local inflammation, but this comes on 
slowly and is insignificant unless prolonged. On the other hand, the 
comparatively insoluble zinc oxide is only a mildly antiseptic and 
stimulative medium, since just sufficient of the salt is dissolved to 
produce this general effect. It therefore finds a use in clinical medi- 
cine as a healing salve to cover exposed and ulcerating surfaces. 

3. The systemic action of zinc after absorption. — The more 
soluble zinc salts are slowly absorbed from abraded surfaces, and par- 
ticularly by the alimentary mucosa. Yet it is claimed that direct 
cases of chronic zinc poisoning are rare, if not entirely absent. 

364 



ACTION OF ZINC AFTER ABSORPTION 365 

However, if a solution of a zinc salt is introduced into the circula- 
tion, a procedure that can be accomplished by using some one of the 
double salts of zinc which does not so readily precipitate protein, 
a cycle of symptoms follows directly due to the toxic action of the 
metal. It has long been known that zinc sulphate is an emetic. 
In the earlier history of medicine a solution of this salt was a favorite 
medium for the production of vomiting. In this instance the ex- 
planation is that the zinc, after absorption, directly stimulates the 
nerve centers concerned in vomiting. With excessive and toxic doses 
death follows, primarily through the paralysis of the nervous system 
and of the cardiac muscle. 

Take it all in all, the zinc salts are considerably less toxic than 
the salts of lead. For therapeutic purposes they are relatively un- 
important. 



CHAPTER LII. 
THE SALTS OF COPPEE. 

I. 
Details of Pharmacological Action. 

The salts of copper, like those of lead and zinc, enter into com- 
bination with protein. This reaction is the foundation of such toxic 
effects as they produce on animal and plant' tissues. The copper 
salts are relatively soluble. The ones most commonly met with in 
pharmacological experiments are copper sulphate, copper acetate, 
and the double salts of copper and arsenic, as the copper arsenite. 

i. General toxic and disinfectant action of copper salts. — Living 
tissues respond with great variation to contact with solutions of 
copper salts. This may be explained in part by the fact that copper 
is normally present in a number of plants and in certain animal 
tissues. As an example, it is a well-known fact that copper takes 
the place of iron in the respiratory pigments of some lower forms 
of animals. The blood of certain species of crustaceans, of which 
the common edible crab is an example, and of certain molluscs, contains 
the respiratory pigment hemocyanin, which differs chemically from 
hemoglobin in that copper displaces the iron of the pigment molecule. 
Fredricq x has shown that hemocyanin chemically unites with oxygen 
in a very unstable combination, comparable with that of oxygen and 
hemoglobin. The oxyhemocyanin, however, is of a pale blue color 
instead of the usual scarlet red, which characterizes oxyhemoglobin. 

It has been shown also that certain plants contain traces of copper. 
However, numerous observations also show that many of the lower 
plant forms are very susceptible to the toxic action of copper. This? 
fact is taken advantage of in the practical purification of water 
supplies, especially in the ridding of reservoirs of the infesting fresh 
water algas. Minute traces of copper, such as are given to the water 
by dragging a sack of copper sulphate through a reservoir, are suffi- 
cient to kill the spirogyra and other species of pond algas. 

Locke has shown that copper salts are toxic to lower forms of 

1 Fredricq, L. : Archives de Zoolbgie Escperimentale, 1878. 

366 



THE ELIMINATION OF COPPER SALTS 367 

animal life. As dilute a solution as one in two hundred thousand 
is sufficient to kill ciliated infusoria and isolated ciliated epithelial 
cells. 

On the other hand, the tissues of man and mammals are relatively 
resistant to the toxic action of copper sulphate. Certain tissues with- 
stand, for a short time, as high a concentration as one per cent., 
though this concentration finally becomes toxic. Some molds are 
said to be resistant to copper, while certain yeasts are very susceptible 
to its action, though copper sulphate is the principal ingredient of the 
well-known Bordeaux mixture which is used as a spray to rid plants 
of fungus diseases. 

2. Systemic symptoms of the action of copper. — Copper salts 
owe their toxicity to the formation of protein compounds, just as in 
the cases of lead and zinc. This property gives them the usual 
astringent action, and with sufficient concentration an irritant and 
corrosive toxic end result. Copper is an old-time emetic, depending 
upon its irritation of the mucous lining of the stomach. It produces 
nausea with pain from local irritation. After absorption the salts 
react chiefly on the nerves and muscles to produce an increase in the 
respiratory rate and a slow weak pulse accompanied by dizziness 
and ending in paralysis or sometimes convulsions. 

Copper salts are not so toxic as lead salts, in fact chronic action 
does not often, if ever, occur. That the continued use of applications 
is detrimental cannot be questioned. Its irritant action on the ali- 
mentary tract when often repeated, as in the use of foods preserved 
with copper cooked in copper vessels, have a tendency to produce a 
gastric and intestinal catarrh and a chain of secondary symptoms 
depending thereon. 

3. The elimination of copper salts. — Copper salts are compara- 
tively easily absorbed from the alimentary tract. They are distributed 
by the blood throughout the body. The liver has been found to con- 
tain a higher percentage of copper, though traces have been observed 
in most every tissue. The metal is slowly eliminated through the 
excretory glands, especially the kidney. However, traces of copper 
have been found in the excretions of the skin and in the hair. It is 
re-excreted into the alimentary canal to a certain extent, chiefly by 
the salivary and digestive glands. A portion of the copper is dis- 
charged from the body in the feces. 



CHAPTER LIII. 
THE MERCURY SALTS. 

I. 

Introductory. 

Mercury is one of the most active of the heavy metals. It is 
toxic in the body, not only from the action of the ions derived from 
the salts, but following the absorption of the metal itself. The most 
common salts of mercury used for pharmacological and medicinal 
purposes are: Mercuric chloride, HgCl 2 , mercurous chloride, Hg 2 Cl 2 , 
mercuric iodide, Hgl 2 , and the metal itself. 

II. 

Outline of Pharmacological Action. 

The most important changes in the behavior of living protoplasm 
introduced by mercury are: 

1. Mercury has a cathartic action on the alimentary canal. 

2. Salts of mercury are highly toxic for micro-organisms. 

3. In very dilute solutions, as one in three hundred thousand or 
less, salts of mercury are stimulative to protoplasm, producing an 
increase in the red blood cells, diuresis, etc. 

4. Salts of mercury, in the more concentrated solutions, are very 
toxic for animal and vegetable protoplasm. 

III. 

Details of Pharmacological Action. 

i. The absorption of salts of mercury. — The extraordinary 
toxicity of mercury depends primarily upon two factors : (1) The rela- 
tive solubility of its salts as compared with other heavy metals ; 
(2) the solubility of its protein compounds in animal fluids. Of 
the different mercury salts calomel or mercurous chloride is com- 
paratively insoluble. When it is introduced into the alimentary 
canal it only slowly dissolves, and is correspondingly slowly absorbed. 

368 



ACTION OF MERCURIAL SALTS OX BACTERIA 369 

This accounts for the fact that relatively large quantities of this 
salt may be swallowed with impunity, since they pass through the 
canal without being absorbed. Mercuric chloride, on the other hand, 
is highly soluble and correspondingly toxic. 

Whenever mercury is brought into contact with either the fluids 
of the body or the tissues, it enters into chemical combination with 
the protein constituents forming protein compounds. Proteins are 
in this way precipitated, but the precipitate, when in small amount, 
is readily soluble in excess of fluid largely on account of the sodium 
chloride content of the body fluids. Mercury, therefore, present in 
the mammalian body takes the form of albuminates. These, in solu- 
tion, pass readily to all parts of the body and lead to the characteristic 
mercurial action. This action is merely stimulative when the sub- 
stance is present in extremely diluted solution, i.e., traces, but strongly 
corrosive when the concentration reaches the toxic level. 

The action of the metal mercury follows when the substance 
enters the body either by absorption of its vapor through the pul- 
monary tracts or by absorption from the skin when the metal is 
applied in the form of a fine emulsion, as in inunction of mercurial 
ointment. 

2. The action of mercurial salts on bacteria and other lower 
forms of life. — Mercury has come to be recognized as one of the 
most valuable of the antiseptic substances. Its soluble mercuric 
chloride is the form used for the purpose of antisepsis and disin- 
fection. It has a powerful and toxic action on the lower forms of 
living matter. For purposes of disinfection, the bichloride in solu- 
tions of one part in one thousand is the strength generally used. 
For the disinfection of excreta and other highly infectious sub- 
stances, other chemicals are probably more available, but a solution 
of bichloride of mercury one part in one thousand will kill all active 
forms of bacteria if allowed to stand in contact a sufficient length 
of time. For many bacteria, one part in a million will inhibit 
growth. Other forms of bacteria, of which the tubercle bacillus is 
an example, are more resistant to the action of mercuric chloride. 
Even one in one thousand must stand in contact with tubercle bacilli 
for several hours to insure their death. Resting spores are naturally 
more resistant and require a more vigorous treatment for steriliza- 
tion, if it be produced by solutions of mercury. 

In surgical procedure, the antiseptic action of mercuric salts is 
relied upon at the present day, where asepsis is not practical. The 
solutions, from the standpoint of the human patient, are bland and 



370 THE MERCURY SALTS 

not acutely irritant, hence not painful. However, in surgical dress- 
ing it must be remembered that the tissues of the body are also sus- 
ceptible to local mercurial poisoning. A prolonged contact with 
stronger antiseptic solutions may lead to superficial irritation and 
possibly necrosis and death of the cells of the area. 

Soluble mercuric salts are also toxic to generalized protoplasm, 
such as infusoria, white blood corpuscles and the like. A solution 
of one in ten thousand is sufficient to inhibit the movement of white 
blood corpuscles. This fact can be demonstrated in the incipient 
stage of inflammation produced by mercuric chloride. An inflam- 
matory process in the frog's web, started by mercuric chloride solu- 
tion, will exhibit the fact that the white corpuscles have lost their 
migratory powers. 

3. The action of mercury on differentiated animal protoplasm. 
— From what has been said above, it is evident that mercuric chloride 
solutions have a varied action on the individual tissues of the animal 
body. In concentrated solutions this action is a toxic one, while 
in the very diluted solutions just the opposite, i.e., a temporary 
beneficial and stimulative effect, may be seen. The concentrated 
solutions convert enough of the protein of the tissues into the 
albuminate to destroy the characteristic cell life. On the other hand, 
the extremely diluted solutions do not bring to the tissues enough 
of the mercurial salts to immediately produce destruction of the 
tissues. In the latter case a very slight formation of albuminate in 
the protoplasm has the rather unexpected effect of increasing the 
activity of the tissues concerned. It is obvious that the increase 
of functional activity in certain tissues will have secondary 
effects that are more or less favorable to the organism as a 
whole. If the intensity of action is toxic and tissue-necrosis 
occurs at any point, then the elimination of function of that 
tissue will lead to secondary actions that are, in the nature of 
the case, injurious to the life of the organism as a whole. One 
need only to refer to the fatal necrosis of the kidney in chronic and 
fatal mercurial poisoning as an example. The favorable action of 
minute quantities of mercury has been taken advantage of by clini- 
cians in certain pathological conditions, for example in anemia follow- 
ing infectious disease. 

Fortunately the margin of safety between the concentration of 
salts of mercury which is toxic for the body tissues and that which 
is toxic for the invading bacteria attacking those tissues is great 
enough to allow of the use of the drug as an antiseptic. This factor 



ACTION ON THE CENTRAL NERVOUS SYSTEM 371 

is particularly applicable for cutaneous surfaces because of the re- 
sistance which the iskin offers to absorption. If an abrasion exists* 
as in the case of an ulcer, or following a surgical operation, or if 
mucous surfaces of the body are to be disinfected with mercurial 
salts, as in the case of the mouth cavity, the rectum, or the vagina, 
then care must be taken lest excessive absorption occur and the body 
receive a toxic quantity of the drug. Keeping in mind these general 
factors, we may examine next the action on particular organs in the 
body. 

4. The action of salts of mercury on the alimentary tract. — Salts 
of mercury have long enjoyed a favorable reputation because of their 
cathartic action. Calomel, or mercurous chloride, because of its 
relative insolubility and correspondingly slow absorption rate, serves 
as a splendid cathartic. Mercuric chloride is violently irritant to 
the alimentary tract, but is available as a purge where it is desirable 
to use only an intense acting drug. The cathartic action of calomel 
depends upon the fact that it is slowly dissolved. Its concentration 
is ordinarily never great enough to produce more than a mild irri- 
tation before it is absorbed from the alimentary tract, hence pro- 
duces a relatively mild cathartic action. The local inflammation 
which it induces in the mucous lining produces only a slight amount 
of exudation, which is favorable from the standpoint of a cathartic. 
The cathartic action of calomel often fails of the final defecation 
reflex, hence leads to an accumulation of refuse in the large intestine. 

Mercuric chloride is violently irritant. It leads not only to local 
inflammation, but induces vigorous reflexes, beginning with those 
from the gastric cavity. As a result the salivary and gastric secre- 
tions are increased and there is a tendency to nausea and vomiting. 
If the action is strong enough, there is an interference with the 
circulation and respiration, and if extremely severe collapse may 
supervene. This last extreme is usually not reached. 

With toxic quantities of mercuric chloride, as in the case of 
accidental poisoning from corrosive tablets, there is rapid absorp- 
tion and enough mercury enters the system to produce acute 
poisoning. In such cases, the poisonous action is prolonged and 
death follows from the continued contact with mercury at the points 
of excretion, particularly in the colon and in the kidney. 

5. Action on the central nervous system. — Salts of mercury are 
relatively inactive so far as the function of the central nervous 
system is concerned. Even in toxic quantities, when the poisonous 
effects proceed to the climax in death, consciousness continues until 






372 THE MERCURY SALTS 

the last. Certain nervous derangements do occur after prolonged 
mercurial poisoning. There is an increased irritability to sensory 
stimulation, a degree of loss of muscular control shown by the feel- 
ing of muscular fatigue and by mercurial palsy. As in lead poison- 
ing the muscular disturbances usually appear first in the upper ex- 
tremities and extend thence over the body. Other local nervous 
symptoms have been described in chronic mercurial poisoning, but 
they are not of sufficient constancy to be enumerated in this con- 
nection. 

6. The action of mercurial salts on the circulatory and respira- 
tory systems. — Of all the parts of the body, the least to be affected 
are the organs of the circulation. The nerve control of the heart 
and blood-vessels remains intact to the last.- The same is true for 
respiration. Such derangements as occur are primarily due to mus- 
cular disturbance in the later toxic action. Experiments indicate 
that the heart, at least of the frog, responds with a more favorable 
rhythm and force in the presence of very dilute solutions of mercuric 
chloride. Strips of cardiac muscle, ventricle of the terrapin, con- 
tracting in physiological solutions, withstand the action of one in 
one thousand solutions of mercuric chloride many minutes, main- 
taining a very uniform rhythm and only slowly decreasing the ampli- 
tude as the muscle protoplasm is slowly coagulated by the mercuric 
salt. 

7. Action of mercury on the kidney. — The kidney, of all the 
organs of the body, is one of the most susceptible to mercurial salts. 
This is no doubt due to the condensation of mercury in the nephridia 
during the process of excretion. Both the glomerulus and the secret- 
ing tubules are sharply affected. The toxic action takes the form of 
irritation, followed by inflammation. There is an early suppression 
of the excretion of urine, accompanied by the presence of blood 
products in the urine, i.e., red corpuscles, albumin, and in many 
cases sugar. As the inflammatory process continues, the renal 
parenchyma undergoes necrosis, and a deposit of calcium salts may 
take place both in the cells and in the cavity of the tubules. Such a 
pathological condition is accompanied by complete anuria leading 
to uremia. 

Very minute quantities of mercury are stimulative to urinary 
secretion. This has been shown by Cohnstein 1 on rabbits. He found 
that an intravenous injection of calomel leads to an increased secre- 

1 Cohnstein, W. : Archiv fur Pathologie und Pharmakologie, Vol. XXX., 
p. 132, 1892. 



THE EXCRETION OF MERCURY 



373 



tion of urine; a fact that has been often observed clinically after 
the administration of the salt. 



The effect of intravenous injection of mercurous chloride on the secretion of urine in the 

rabbit (Cohnstein). 



Period op Secretion. 


Amount of urine per ten minutes. 


Rabbit No. 16. 


Rabbit No. 17. 


1. Normal 


.15 cc. 

.13 cc. 

.16cc. 

.01 cc. 
9.21 cc. 
4.47 cc. 
2.75 cc. 


1.01 CC. 


2. " 


0.87 cc. 


3. " 

Dose Hg 2 Cl 2 in jugular 


0.87 cc. 
.004 cc. 


4. Mercury 


3 09 cc. 


5. " 


5.95 cc. 


6. " 


5 96 cc. 







These experiments indicate an increase in the secretion of urine 
of from one to six and more, per unit of time. 

This effect on the kidney is probably due to direct stimulative 
action of small quantities of mercury on the renal epithelium, an 
action which can and does readily pass over to one of toxic injury as 
expressed in inflammation and necrosis. A different explanation 
has been offered, namely, that the great fluidity of the intestinal con- 
tent in the region of the large intestine leads to a hydremia, and that 
this condition indirectly stimulates the kidneys to a greater secretion. 

8. The excretion of mercury. — The formation of albuminates of 
mercury tends to the storage of this metal in the body tissues. The 
complete secretion of mercury, therefore, takes place only after a 
long interval. Indeed, mercury may be found in the excretions of 
the body for months after its last administration. However, the 
elimination of mercury begins within a few minutes after its absorp- 
tion and its slow excretion continues until its ultimate removal. 
The channels by which the mercury leaves the body are the 
alimentary canal on the one hand, and the kidney and skin on the 
other. All intestinal and cutaneous glands excrete mercury. It 
is thought that the greater portion leaves the body by way of 
the kidney, except in cases of extreme cathartic action. This state- 
ment applies, of course, only to mercury after absorption. The 
large amount lost by way of the alimentary canal after absorp- 
tion is that thrown off in the secretion of the salivary, gastric, and 
pancreatic glands, and by the intestinal mucosa itself. It is gen- 
erally claimed that the mucosa excretes a large percentage of the 



374 THE MERCURY SALTS 

salts of mercury. Mercury, as was found to be the case also with 
lead, detected in the epithelial cells of the colon and rectum is con- 
sidered to be excretion mercury, not mercury in the process of ab- 
sorption. 

A number of the local effects of mercury, especially observed 
in chronic mercurial poisoning, are due to its condensation at the 
point of excretion. Salivation is an example, as is also mercurial 
nephritis, and the ulceration that occurs in the lower bowel and at 
points on the skin. 

9. Acute toxic action of mercury. — Cases of mercurial poisoning 
are more or less common, and generally arise from the actions of 
the soluble mercuric chloride or corrosive sublimate. The solubility 
of this salt and the rapidity with which it is absorbed accounts for 
the chain of symptoms which characterize the condition. The 
primary effects are due to the local irritation of the alimentary 
tract. There is acute gastritis accompanied by nausea, usually vomit- 
ing and diarrhea with intense griping pains. If the inflammation 
has progressed far enough the vomit will contain flecks of blood, 
and sometimes disintegrated epithelium from the corrosion of 
the mucous membrane. The stools are usually voluminous and 
watery, and may also contain, besides the usual fecal matter, dis- 
integrated epithelial tissue. These symptoms occur almost immedi- 
ately, certainly within a few hours. If the corrosion is unusually 
severe there is a degree of collapse from the extensive visceral 
reflexes. 

The acute symptoms occurring from action of mercury after 
absorption are those which might be expected from the coagulation 
of the protoplasm of the tissues in various portions of the body. The 
most important of all is acute nephritis with suppression of the urine. 
A weak and irregular heartbeat also follows, with low blood-pressure, 
and an increase in the secretion of saliva and of perspiration. "While 
there may be muscular weakness, the general muscular and nervous 
reactions are little if at all interfered with. 

10. Chronic mercurial poisoning. — Chronic mercurial poison- 
ing, called mercurialism, occurs after prolonged absorption of 
the salts of mercury. This class of toxic action is rendered more 
common because of the widespread use of mercury in the treatment 
of syphilis and other venereal infections. The early symptoms are 
found in inflammation of the mouth, including the gums, and an 
increase in the secretion of saliva or insalivation. The inflammatory 
process about the gums may progress to an actual necrosis, beginning 






CHRONIC MERCURIAL POISONING 375 

in the bone around the bases of the teeth and involving more or less 
of the jawbones. 

The alimentary canal shows the effect of the poison especially 
along the lengths of the intestine, particularly the large intestine. 
This usually takes the form of chronic diarrhea. The concentration 
of the action at this point is presumably associated with its excre- 
tion here.* 

Other regions through which mercury is excreted begin to show 
the effect of its toxic action. For example the irritant effect on 
the skin leads to local foci of an erythematous type of inflammation, 
usually in association with the sweat glands. This is to be attributed 
to the direct action of the mercury as a result of the cutaneous 
excretion. 

The chronic effects of mercury on the kidney have already been 
indicated. Following the acute suppression of function arid the 
beginning of renal inflammation, there is a progressive degeneration 
especially of the secreting cells of the convoluted tubules. The 
glomeruli are also involved in this necrosis. When the lesion is 
extensive enough, it leads to a failure to excrete the waste products of 
the body, and therefore to general toxic uremia and death. It is evi- 
dent that a poison so toxic in its action will produce an inevitable 
depression of metabolism. This is shown in the general weakness and 
in the final anemic condition of the victim. 




CHAPTER LIV. 
SALTS OF SILVER. 

I. 

Details of Pharmacological Action. 

Silver nitrate has long been extensively used for medicinal pur- 
poses, but in recent years has been more or less displaced by a num- 
ber of organic silver compounds. Of the organic compounds, the 
silver vitellate and silver caseinate are soluble in water and not pre- 
cipitated by the albumin or the chlorides of the blood. 

i. The local and antiseptic action of silver salts. — For many 
years the fused silver nitrate crystals have been used locally as 
a caustic for mucous surfaces and especially for local infections. 
When a cauterizing stick is applied to a mucous surface, the nitrate 
crystals begin to dissolve and to form a surface film of albuminate. 
The action is strongly antiseptic, destroying the infectious bacteria 
as well as the surface albumin. The irritant action of silver nitrate 
depends upon the formation of this local eschar. Silver, like lead, 
prevents its own rapid and extensive absorption by the process of 
precipitation of albumin. But silver is more irritant than lead, 
though less astringent. 

Solutions of silver nitrate are disinfectants for mucous mem- 
branes. They have been used especially to combat local infection of 
the mouth and throat, for the disinfection of the eyes and rather ex- 
tensively for the disinfection of the uro-genital apparatus. 

The soluble organic preparations of silver are not precipitated 
by albumins and are non-irritant. Therefore, a higher percentage 
of silver may be brought in contact with surfaces in this form. 

2. The toxic action of silver salts. — Silver poisoning by the 
accidental swallowing of lunar caustic or from the accidental injec- 
tion of silver nitrate has occurred. Crystallized nitrate in the 
stomach dissolves rapidly and forms extensive local lesions. These 
are accompanied by a precipitation of albumin over the surface of 
the mucosa. This is followed by inflammation with intense burning 
pain, and still later by extensive corrosion, which may terminate 

376 




SYSTEMIC EFFECTS 377 

fatally. A fatal case from 30 grains taken by an adult has been re- 
ported, while half that quantity swallowed as lunar caustic proved 
fatal in a child of fifteen months. 

The accidental subcutaneous injection of a four per cent, solu- 
tion of silver nitrate is reported to have been accompanied by intense 
burning pain, followed in a couple of hours by more general deep- 
seated pains associated with the bones of the neighboring parts. 
In twenty-four hours the injected tissues appeared pale and began 
to slough. Extensive inflammation occurred in the neighboring tis- 
sues and extended for some distance along the lymphatic channels. 
Healing in such cases is extremely slow, apparently from inter- 
ference with a sufficient vascular supply. 

3. Systemic effects. — The general systemic effects of silver are 
not extensive. This is due to the formation of soluble silver com- 
pounds and the elimination of this salt from toxic activity. If given 
by way of the mouth, silver solutions are in part transformed into 
insoluble lead sulphides and are lost with the feces. Absorption 
albuminates are formed, converting the silver to a less active form. 
Certain toxic nerve effects have been described. The spinal cord and 
the medulla are slightly stimulated at first, then general paralysis 
is produced. The various automatic centers in the medulla are 
involved in this process, especially the vasomotor, cardio-inhibi- 
tory, and the respiratory centers. Cohnstein describes a striking 
increase in renal secretion in the rabbit after ten milligram doses 
of silver chloride in solution in sodium hyposulphite given subcuta- 
neously. In one experiment the urine per hour was increased from 
1.64 to 11.60 grams; in another experiment from 1.50 to 6.39 grams. 
He records only a trace of albumin in the urine in a single experi- 
ment. However, silver salts have not been described as excreted by 
the urine. 

Silver that has been absorbed becomes fixed in various organs, 
particularly in the connective tissues and muscles, where it is pre- 
cipitated in insoluble form. In the continued clinical use of silver 
salts it lias been known for many years that precipitation of the silver 
in the connective tissues leads to a permanent pigmentation. Ex- 
tensive deposits of silver lake place in the subdernial connective tissue. 
giving to the unfortunate a peculiar bluish color known as argyria. 
This pigmentation is permanent, at least we have found no means for 
its removal up to the present time, unless the solvent action of hexa- 
methylamine, described by Dr. Crispin, proves the efficient agenl (see 
note, page 337 ) . 



CHAPTER LV. 
SALTS OF BISMUTH. 



Details of Pharmacological Action. 

Bismuth is still another heavy metal that possesses therapeutic 
interest of high degree. The soluble salts of -bismuth are readily 
absorbed and toxic. These are the bismuth salts of certain inorganic 
acids, especially bismuth ammonium citrate. The insoluble salts 
bismuth subnitrate, subcarbonate, also bismuth subcitrate as well as 
certain other bismuth organic compounds that are not soluble in 
water, are only slightly soluble in the body fluids. These salts are 
non-toxic. 

i. The action of soluble bismuth compounds. — Soluble bismuth 
compounds are toxic after introduction into the system, and poison- 
ous effects are similar to that of certain other heavy metals, perhaps 
to mercury more than to any other. In the nervous system the toxic 
action falls heavily on the spinal cord and medulla. The symptoms 
are those of strong stimulation accompanied by rapid respiration, by 
muscular cramps, and generally by vomiting, later by motor paralysis 
and consequent suppression of respiration. The action on the cir- 
culatory system affects primarily the cardiac muscle, leading to 
weak circulation. In the symptoms of salivation and stomatitis, 
comparable to that of mercurialism which has been described, there 
is a tendency to diarrhea with ulceration and often necrosis of the 
large intestine, and to nephritis. 

The toxic action of bismuth sometimes appears from the exten- 
sive application of insoluble salts to ulcerating surfaces. This un- 
doubtedly depends upon some unknown condition favoring solution 
and absorption of the basic compounds. 

2. The action of insoluble bismuth salts. — The insoluble bismuth 
salts have, in recent years, widely extended use, especially in con- 
nection with the study of the alimentary tract by the Kontgen-ray 
method. Bismuth subnitrate, which is the usual salt used for this 
purpose, is very opaque to the rays, hence gives a sharp picture of 

378 



DETAILS OF PHARMACOLOGICAL ACTION 379 

the boundaries of the alimentary cavities. Difficult physiological 
problems as regards the alimentary movements have been explained 
by this method. Notable among these are the studies of Cannon ' 
on the movements of the stomach and of the intestines. Preparations 
of the bismuth subnitrate are also used for certain Rontgen-ray pic- 
tures of the uro-genital apparatus, particularly of the ureters and of 
the pelvis of the kidney. No untoward results come from this 
treatment, either in man or mammals. 

The subnitrate of bismuth is absorbent. When brought in contact 
with the living tissues, as in the case of the surface of an ulcer or 
the mucosa of the alimentary canal, it acts as an absorbent and a 
mild antiseptic. The antiseptic properties are due to the solution 
of traces of the bismuth. This is explained by the solvent action 
of the tissue fluids. In the case of the stomach, if there is an ex- 
cessive secretion of hydrochloric acid in the gastric juices, a portion 
of the subnitrate will be reduced, giving rise to a small amount of 
bismuth chloride. The subnitrate remaining insoluble is carried for- 
ward along the canal by the peristalses. The traces of soluble salts 
are absorbed and enter the circulation and are excreted by the kidney. 

When bismuth subnitrate passes the cecum it meets and reacts 
with the sulphides, which are present in greater or less quantities 
in the large intestine, thus forming bismuth sulphide. The sulphide 
has a toxic influence, not only on the mucosa, but on the capillaries 
and smaller blood-vessels of the intestinal wall. Whether the bismuth 
sulphide acts to obstruct the circulation by small thrombi, as has been 
claimed, or by other toxic influences, it results in a tendency to 
ulceration with necrosis in local areas. In general, bismuth has a 
slight sedative influence on the movements of the alimentary canal, 
probably due largely to the reduction of the subnitrate by such salts 
as sodium sulphate, thus eliminating the stimulative effects of the 
sulphate ion. Bacteria, which produce fermentation in the large 
intestine of the animal body, have a tendency to liberate 
nitrites from the bismuth subnitrate, a process that has been de- 
scribed by B6hme. a He found in tests on the rabbit that after the 
introduction of subnitrate of bismuth into the loop of the large in- 
testine the urine of the animal reacted strongly to tests for nitrites 

1 Cannon, W. B. : The American Journal of Physiology, Vol. L, p. 359, 1898; 
Vol. VI., p. 251, 1902. 

2 Bohme, A.: " Uber Nitritvergiftung nach interner Darreichung von Bis 
muthum subnitricum," Archiv fur experimentalle Pathologie und Pharmakologie, 
Vol. LVIL, p. 441, 1907. 



380 SALTS OF BISMUTH 

within a few hours. He also showed that nitrites could be detected 
in the blood of the animal. The toxic influence of nitrites from this 
source are sufficient to produce death of an animal (see nitrites, page 
178). 



DOSE TABLE FOR THE MORE IMPORTANT DRUGS 

NOW IN USE. 

The following Dose Table contains the average individual doses 
and the maximum doses. The average dosage is taken from Useful 
Remedies, compiled by the Council on Pharmacy and Chemistry of 
the American Medical Association, and published by the American 
Medical Association Press. The maximum dosage is taken from 
William Wood and Company's Physician's Diary for 1914. 

APPENDIX. 

Adult Doses (by the mouth) 



Drug. 



Acetanilide 

Acet-phenetidin .... 
Acid, aceticum dil. . 
Acid, benzoicum . . . 

Acid, boricum 

Acid, carbolicum . . 
Acid, citricum .... 
Acid. hydrochlori- 

cum dil 

Acid, hvdrocyanicum 

dil. * 

Acid, salicylicum . . 
Acid, tannicum 
Aconiti tinctura . . 

Aconitina 

Adrenaline, 1/1000. 

(See epinephrine) 

^Ether 

JEtheris nitrosi spir- 

itus 

yEtheris spiritus . . . 
^Etheris spiritus 

compositus 

Aloe 

Aloes extr 

Aloes tinct 

Aloin 

Ammoniacum 

Ammoniac spiritus.. 
Amnionii chloriduni 
Ammonii phosphas. 
Amyl nitris 



Average Dose. 



0.25 gm. 
0.5 gm. 



0.5 gm. 
0.5 gm. 



0.5 gm. 
1.00 cc. 



0.1 
0.5 
0.5 
0.6 



cc. 
gm. 
gm. 
cc. 



0.5 cc. 
1.00 cc. 

2.00 cc. 
4.00 cc. 

4.00 cc. 
0.250 gm. 
0.125 gm. 



0.065. gm. 



0.5 gm. 
0.2 cc. 



4 gr. 
7.5 gr. 



7.5 gr. 

7.5 gr. 



7.5 gr. 

15 min. 

1.5 min. 

7.5 gr. 

7.5 gr. 

10 min. 



7.5 min. 
15 min. 



30 

1 

1 
4 
o 



nun. 
fl. dr 

il. dr 

gr. 

gr. 



1 gr- 



7.5 gr. 

3 min. 

381 



Maximum Dose. 



0.50 gm. 

1.00 gm. 

4.00 cc. 

2.00 gm. 

1.00 gm. 

0.13 gm. 

2.00 gm. 

2.00 cc. 

0.20 cc. 

1.30 gm. 

0.65 gm. 

0.30 cc. 
0.00026 gm. 



1.00 
4.00 

s.oo 

6.00 

6.00 
0.65 
0.65 
8.00 
0.20 
2.00 
4.00 
0.65 
1.30 
0.30 



cc. 
cc. 

cc. 
cc. 

cc. 
gm 
gm 
cc. 
gm 
gm 
cc. 
gm 
gm 
cc. 



8 
16 

1 
30 
15 

2 
30 

30 

3 
20 
10 

5 



gr. 
gr. 
dr. (Troy) 

gr- 
gr- 
gr- 
gr- 

min. 

min. 

gr. 

gr- 
min. 



1/250 gr. 

15 min. 

1 fl. dr. 

2 dr. (Troy) 
1.5 dr. (Troy) 

1.5 dr. (Troy) 
10 

gr. 

dr.(Ti 

gr. 

gr. 

dr. (Troy) 

gr. 

gr. 

min. 



382 DOSE TABLE FOR THE MORE IMPORTANT DRUGS NOW IN USE 



Adult Doses (by the mouth). — Continued. 



Drug. 



Antimonii et potas- 
sii tartras (emet- 
ic) 

Antipyrin 

Apocynum 

Apomorphinse hydro- 
chloras (emetic) . 

Argenti lactas 

Argenti nitras 

Arsenii iodidum . . . 

Aspirin 

Atophan 

Atropine sulphas . . . 



Average Dose. 



Barii chloridum . . . 
Belladonnas foliorum 

tinct 

Belladonnas radix . . . 

Benzoini tinct 

Bismuthi citras . . . 
Bismuthi subnitras. 



0.03 
0.25 



gin. 
gm. 



mg. 



0.01 gm. 



0.5 gm. 



0.4 mg. 



0.5 cc. 



Caffeina 

Caffeina citrata . 
Caffeinae sulphas . 
Calcii chloridum . 
Calcii hypophosphis 

Calomel 

Camphorse spiritus 

Cantharis 

Cantharidis tinct. . 
Cascara sagrada ext. 

Chloral 

Chloretone 

Chloroformum . . . 
Chichonse tinct. . . . 

Coca 

Cocainse hydrochlo- 

ras 

Codeina 

Conine 

Copaiba 

Creosotum 

Cupri arsenitis 
Cupri sulphas 

(emetic) ' 

Curare 



0.5 gm. 

0.065 gm. 
0.125 gm. 



0.5 gm. 
0.5 gm. 
0.065 gm. 
1.00 cc. 



0.5 gr. 
4 gr. 



0.1 gr. 
6.5 gr. 



7.5 gr. 
1/160 gr. 



7.5 gr. 



gr. 
gr. 



gm. 



Digitaline (cryst. 

Nativelle ) .... 
Digitalis extr. fl.. 
Digitalis tinct. . . 



Elaterium 



0.15 cc. 
4.00 cc. 



0.03 gm. 
0.03 gm. 



1.00 cc. 
0.2 cc. 



0.25 gm. 



7.5 
7.5 
1 
15 



gr. 

gr. 

min. 



15 gr. 



mm. 
fl. dr. 



0.5 gr. 
0.5 gr. 



15 

3 



min. 
min. 



gr. 



1.00 cc. 
0.005 gm. 



15 min. 
0.1 gr. 



Maximum Dose. 



0.06 gm. 
1.00 gm. 
1.30 gm. 

0.006 gm. 
0.32 gm. 



0.06 
0.01 
2.00 
1.00 



gm. 
gm. 
gm. 
gm. 



0.00065 gm. 

0.065 gm. 

1.00 cc. 

0.06 gm. 

2.00 cc. 

0.30 gm. 

2.00 gm. 



0.20 
0.32 
0.30 
1.30 
1.00 
1.30 
2.00 
0.03 
0.65 
0.50 
2.00 
0.65 
0.65 
8.00 
8.00 



gm. 

gm. 

gm. 

gm. 

gm. 

gm. 

cc. 

gm. 

cc. 

gm. 

gm. 

gm. 

cc. 

cc. 

cc. 



0.13 gm. 
0.65 gm. 
0.006 gm. 
2.00 cc. 
0.30 cc. 
0.0006 gm. 

0.32 gm. 
0.006 gm. 



0.002 gm. 
0.12 cc. 
1.30 cc. 

0.004 gm. 



gr- 
gr- 
gr. 



0.1 gr. 
5 gr. 

1 gr- 

1/6 gr. 
30 gr. 
15 gr. 

0.01 gr. 

1 gr. 



mm. 

gr- 
min. 

gr- 
gr. 

gr. 
gr. 
gr- 
gr- 
gr- 
gr- 
min. 



0.5 gr. 
10 min. 



gr. 

gr- 

gr- 

min. 

fl. dr. 

gr- 



2 dr. (Troy) 

1 gr. 

0.1 gr. 

30 min. 

4 min. 
0.01 gr. 

5 gr. 
0.1 gr. 



1/30 gr. 
2 min. 
20 min. 

1/16 gr. 



DOSE TABLE FOR THE MORE IMPORTANT DRUGS NOW IN USE 383 



Adult Doses (by the mouth). — Continued. 



Drug. 



Average Dose. 



Emetina (alkaloid) . 

Epinephrine, 1/1000 
Ergota fl. ext. 

Eserina 

Eserinae salicylas . . 

Eucainae hydrochlo- 

ras /3 



0.5 cc. 
2.00 cc. 



0.001 gr. 



Ferri arsenas 

Ferri chloridum . . . 
Ferri chloridi tinct. 
Ferri et quininee ci- 

tras 

Ferri et strychnine 

citras 

Frangulae extr. fl. . . 



Gaultheriae oleum . . 
Gelsemina ( alka- 
loid) 

Gelsemii extr. fl.. . . 

Gentianae extr 

Glonoin 



Heroin 

Homatropinae hydro- 
bromas 

Hydrargyri chlori- 
dum corros 

Hydrargyri massa . . 

Hydrastinae hydro- 
chloras 

Hydrastis tinct. . . . 

Hyoscinae hydrobro- 
mas 

Hyoscyaminae hydro- 
bromas 



Iodi tinct. 
Iodothvrin 



Jalapae resina 
Litliii citras . 



Magnesia 

Magnesii citras 

granulatus .... 
Magnesii sulphas 

Manna 

Menthae piperita 

aqua 



0.5 



0.25 gm. 



0.003 gm. 

0.0005 gm. 

0.003 gm. 
0.250 gm. 



7.5 min. 
30 min. 



0.065 gr. 



gr. 



0.05 gr. 

1/128 gr. 

1/20 gr. 
4 gr. 



2.00 gm. 



16 



gm. 



30 



gr. 



240 



gr. 



Maximum Dose. 



( 0.002 gm. 

] to 

( 0.02 gm. 

1 cc. 

4.00 cc. 

0.0013 gm. 

0.003 gm. 

2.00 cc. 

0.006 gm. 
0.25 gm. 
2.00 cc. 

0.65 gm. 

0.12 gm. 
2.00 cc. 

1.00 cc. 

0.003 gm. 
0.65 cc. 
0.65 gm. 
0.001 gm. 

0.01 gm. 

0.003 gm. 

0.006 gm. 
0.40 gm. 

0.65 gm. 
4.00 cc. 



0.001 gm. 

0.001 gm. 

0.32 cc. 
1.30 gm. 

0.40 gm. 

1.80 gm. 

4.00 gm. 



, 30.00 gm. 

30.oo gm. 

i 30.00 gm. 

16.00 cc. 



1/30 gr. 
to 

1/3 gr. 
15 min. 
1 dr. 
1/50 gr. 
1/20 gr. 

30 min. 

6^ c sol. 
0.1 gr. 



min. 



10 gr. 



gr ; 

min. 



1/29 gr. 
10 min. 
10 gr. 

1/60 gr. 

1/6 gr. 

0.05 gr. 

0.1 gr. 
6 gr. 

1 gr. 

1 dr. (Troy) 

1/60 gr. 

1/60 gr. 

5 min. 
20 err. 



gr. 

gr- 

dr. (Troy) 

oz.n < 

OZ.I I 

OZ. ('I I 

dr. (Troy) 



384 DOSE TABLE FOR THE MORE IMPORTANT DRUGS NOW IN USE 



Adult Doses (by the mouth). — Continued. 



Drug. 



piperita? 



Menthae 

spiritus 

Menthol 

Methylis salicylas . 
Monobrom - acetani - 

lide 

Morphina 

Morphinae hydro- 

chloras 
Morphinse sulphas . . 
Morrhuae oleum . . . 
Muscarine nitras . . 
Myrrhae tinct 



Naphthol p.. 

Nicotinum 

Nitroglycerinum . . . 
Nucis vomicae extr. . 
Nucis vomicae tinct 



Opium 

Ouabain 

Ovariin 



Pancrea tin 

Papain 

Para-acet-phenetidin 

Pepsinum 

Phenacetine 

Phenol ( absolute ) . . 

Phenolphthalein . . . 

Phosphorus 

Physostigmatis extr. 

Physostigminae sul- 
phas 

Pilocarpina 

Pilocarpinae hydro- 
chloras 

Plumbi acetas 

Podophyllum 

Podophylli extr. . . . 

Podophyllin 

Potassii acetas .... 

Potassii bromidum . 

Potassii citras 

Potassi cyanidum . . 

Potassii et sodii tar- 
tras 

Potassii iodidum... 

Potassi sulphas . . . 

Quillaiae tinct. (1 to 
10) 

Quininae hydrobro- 
mas 



Average Dose. 



2 cc. 
0.065 gm. 
1 cc. 



0.01 gm. 

0.015 gm. 
0.015 gm. 
16 cc. 



0.015 gm. 
0.6 cc. 



0.5 



0.25 gm. 



0.065 gm. 
0.1 gm. 
0.5 mg. 



mg. 



0.01 gm. 
0.065 gm. 
0.015 gm. 



2 gm. 
1 gm. 
1 gm. 



8 gm. 
0.5 gm. 



30 

1 

15 



mm. 
gr. 



0.20 gr. 

0.25 gr. 

0.25 gr. 

4 fl. dr. 



15 



0.25 gr. 
10 min. 



7.5 gr. 



gr. 



1 gr. 

1.5 gr. 

1/125 gr. 



1/62 gr. 



0.20 gr. 
1 gr. 
0.25 gr. 



30 
15 
15 



gr. 
gr. 



120 gr. 
7.5 gr. 



Maximum Dose. 



1.00 cc. 
0.065 gm. 
2.00 cc. 



1.00 
0.03 



gm. 
gm. 



0.03 gm. 

0.03 gm. 

16.00 cc. 

0.06 gm. 

1.00 cc. 

0.30 gm. 
0.001 gm. 
0.001 gm. 
0.03 gm. 
1.30 cc. 

0.12 gm. 
0.00026 gm. 
0.36 gm. 



2.00 
0.50 
1.00 
1.30 
1.00 
0.20 
2.00 



gm. 

gm. 

gm. 

gm. 

gm. 

cc. 

gm. 



0.0013 gm. 
0.006 gm. 

0.0006 gm. 
0.05 gm. 



0.05 
0.20 
1.30 
0.32 
0.03 
2.00 
2.65 
4.00 



gm. 
gm. 
gm. 
gm. 
gm. 
gm. 
gm. 
gm. 



0.0065 gm. 



1.30 
16.00 



gm. 
gm. 



4.00 cc. 
1.30 gm. 



15 min. 

1 gr. 
30 min. 

15 gr. 
0.5 gr. 

0.5 gr. 
0.5 gr. 

4 dr. (Troy) 

1 gr. 
15 min. 

5 gr. 
1/60 gr. 
1/60 gr. 

0.5 gr. 

20 min. 

2 gr. 
1/250 gr. 

6 gr. 



g r - 
gr. 
gr. 
gr- 
gr- 
gr- 
gr- 



1/50 gr. 
0.1 gr. 

0.01 gr. 
0.75 gr. 



0.75 gr. 



3 
20 

5 

0.5 
30 
40 

1 

0.1 

1 

20 

4 



gr- 
gr- 
gr- 

gr- 
gr. 
gr- 
dr. (Troy) 

gr- 

oz. 

gr- 

dr. (Troy) 



1 dr. (Troy) 
20 gr. 



DOSE TABLE FOR THE MORE IMPORTANT DRUGS NOW IX USE 
Adult Doses (by the mouth).— Continued. 



Drug. 


Average Dose. 


Maximum Doee. 


Quininae hydrochlo- 

ras 

Quininae sulphas . . . 

Rhamni purshianae 

extr. fl 

Rhei extr. fl 

Rosein (Fuchsin) . . 


0.25 
0.25 

1.00 


gm. 
gm. 

cc. 




4 
4 

15 


gr. 
gr- 

min. 



1.00 gm. 
1.00 gm. 

16.00 cc. 
2. no cc. 
0.25 gm. 

2.00 gm. 
4.00 

0.20 gin. 
0.20 cc. 
4.00 cc. 

0.001 gm. 


15 gr. 
15 gr. 

4 dr. (Troy) 
30 min. 
4 gr. 

30 g 
1 dr. (Troy) 

3 


Salol 




Sarsaparillae ext. fl. 






Scilla 


0.125 gm. 


2 


gr- 


Scillae extr. fl. 


Scillae syr 

Scopolamine hydro- 

bromate 

Senna 


2 

0.5 
4 
2 
4 


cc. 

mg. 
gm. 
cc. 
cc. 


30 

l/12c 

60 

30 

1 


min. 

Igr. 
gr. 

min. 
fl. dr. 


1 dr.iT: 
1/64 gr. 


Sennae extr. fl 

Sennae svr 


16.00 cc. 


4 dr. (Troy) 


Serpentaria 


2.00 gm. 
0.008 gm. 
4.00 gm. 
4.00 gm. 
4.00 gm. 
4.00 gm. 
2.00 gm. 
30.00 gm. 
0.005 gm. 
0.006 gm 
0.005 gm. 
0.30 gm. 

4.00 gm. 
1.30 gm. 
0.30 gm. 
0.12 gm. 

0.50 gm. 
0.40 cc. 

4.00 gm. 

4.00 
0.003 gm. 

0.20 oc. 

0.12 gm 

2.oo gm. 


30 gr. 
1/8 gr. 

1 dr. (Troy) 
1 dr.(Ti 
1 dr.(Ti 


Sodii arsenas 

Sodii bicarbonas . . . 
Sodii bromidum . . . 
Sodii citras 


5 
1 

1 


mg. 
gm. 
gm. 


0.1 

15 
15 


g r - 
gr- 
gr- 


Sodii phosphas .... 

Sodii sulphas 

Strophantin(g) . . . 
Strvehninae nitras.. 


2 

16 
0.3 


gm. 
gm. 
gm. 
mg. 


30 gr. 

15 gr. 

240 gr. 

1/200 gr. 


1 d] 
30 | 
1 oz.(Ti 
1/12 gr. 
0.1 gr. 


Strvehninae sulphas. 
Suprarenal gland . . 


1 


mg. 


1/64 


gr. 


1/12 gr. 
5 gr. 


Taraxaci extr. fl. . . 






1 fir. (T: 


Terpin hydras 

Theobromine 

Thvmol 


0.125 gm. 
0.3 gm. 
0.125 gm. 


2 
5 
2 


gr. 
gr. 
gr. 


20 gr. 
5 gr. 
2 gr. 
8 gr. 


Thvroid extract . . . 


Trimethvlamina . . . 






min. 


Urethane 






1 dr.i'l: 


Valerianae extr. fl. . . 
Veratrina 


2.00 


cc. 


30 


min. 


1 dr.(Ti 
0.05 gr. 


Veratri viridis extr. 
fl. 




3 min. 


Zinci acetas 

Zinci sulphas (emet- 
ic) 


0.125 gm. 
1 gm. 


2 

15 


gr. 

gr. 


2 

Jr. 







INDEX 



Acetanilide, 232, 23G; and see Antipy- 
retics, coal tar 
Acetic acid, 326, 327 
Acetphenetidine, 232, 236; and see An- 
tipyretics, coal tar 
Acetyl-salicylic acid, 246 
Acid, acetic, 326, 327 

acetyl-salicylic, 246 

arsenic, 350 

cacodylic, 350 

carbolic, see Phenol 

citric, 326, 327 

crotonoleic, 281 

dicacodylic, 350 

ergotinic, 165 

hydrochloric, 326 

hydrocyanic, 197 

nitric, 326 

phenol-sulphuric, 239 

prussic, see Hydrocyanic acid 

salicylic, 238, 244 

sulphuric, 326 

tartaric, 326, 327 

tropic, 112 

uric, 90 
Acids, 326 

dilute, action of, 326 

mineral, 326 

organic, 326, 327 
Aconine, 201 
Aconite, 201 

action of. 201, 202 
antipyrei ic, 20 I 
on blood-vessels, 204 
on central nervous system, 202 
on circulatory system, 203 
on glands, 204 
Bummary of, 205 
mic, 202 

and Vera! rine group, 201 

chemical, 201 

historical 201 
Aconitine, 201 
Aconil inn napellus, 201 
Adrenaline, 152; and see Epinephrine 
Age, dosage proportioned to, 7 

influence of. 7 

Agroste a githago, 105 

Albumin compounds of metal, 
Albuminates, metal, formation ol 
Alcohol, 10 

as B local irritant. 20 

chemical relationships <»f, in 



Alcohol, effects of, local, 20, 37 
summary of, 37 
systemic, 22 
elimination of, 36 
group of drugs, 19 
habit, and disease, 37 
local action of, 20 

effects of, on mouth, 21 
on skin, 20 , 
on stomach, 21 
percentage of, in liquors. 20 
systemic effects of, 22, 37 
on blood, 32 

on cardiac centers in medulla, 30 
on circulatory system, 27, 31 
on digestive tract, 33 
on fertility, 36 
on germ-plasm, 36 
on heart, 27, 28, 30 
on liver, 34 
on metabolism, .'!.") 
on muscular tissue, 26 
on nervous system, 22, 23, 24, 

25, 30 
on peripheral blood-vessels, 31 
on respiratory system, 33 
tolerance of, 36 

toxicity of various forms of. 20 
Alcoholization, 22 
Alkalis. 324 

cauterizing action of, 325 
physiological action (^'. 325 
Aloes, 278; and see Vegetable cathartics 
Alpha-eucaine, 219 
Amanita muscarius, 128 
Ammonium carbonate, 32 i 
chloride, ::«'7 
hydrate, 324 
307 
;ict ion of. on secrel iona 

on nervous bj stem, 308 
excretion of. 
Amygdalin, L97 

Amy] nitrite. I7s ; and n < Nitrites 
Anesthesia, stages of. ij. 10, 

Ancstli.'t i, 

Ani- 

Anthi iup "i' eathari ics, pi 

f ive ad ion of 

Vntiaris, 181 
Ant imony 

Antipyren 8; and tet Antipy- 

ret Ecs. coal 'i i 






388 



INDEX 



Antipyretics, coal tar, 321 
action of, 233 

general antipyretic, 233 
narcotic, 234, 235 
on blood, 235 
on blood-vessels, 235 
on central nervous system, 234 
on circulation, 234 
chemical, 231 
comparison of, 236 
historical, 231 
susceptibility to, 235 
Antiseptics, coal tar, 237 
action of, 239, 243 
corrosive, 241 

on central nervous system, 240 
on circulatory system, 241 
on protoplasm, 239 
summary of, 243 
toxic, 239 
chemical, 237 
excretion of, 241 
historical, 237 
toxicology of, 241 
Antitoxins, 261, 266 
Apocodeine, 84 
action of, 84 

on alimentary canal, 87 
on nervous structures, 87 
on urinary motor system, 87 
and pharmacological investigation, 
88 
Apocynum, 181 
Apomorphine, 84 
action of, 84 

on central nervous system, 85 
on muscular tissue, 86 
Argyria, 337, 377 

Arrow poison, 107; and see Curare 
Arsanilates, 354 
Arsenic, 350 

action of, 351 

on alimentary tract, 352 
on circulatory system, 352 
on metabolism, 353 
compounds of, 350 
excretion of, 353 
historical, 350 
organic compounds of, 354 
synthetic compounds of, 350, 354 
toxicity of compounds of, 351 
Arsenic acid, 350; and see Arsenic 
Arseno-benzol, 350, 355; and see Ar- 
senic 
Aspirin, 232, 246 ; and see Antipyretics, 

coal tar 
Atoxyl, 350, 354; and see Arsenic 
Atropa belladonna, 112 
Atropine, 112 

action of, 112, 113. 120 
general symptoms of, 113 



Atropine, action of, on alimentary 
canal, 118 
on bladder, 119 

on central nervous system, 113 
on circulatory system, 116 
on eye, 114 
on glands, 115 
on heart, 117 
on intestine, 118 
on stomach, 118 
on uro-genital apparatus, 119 
summary of, 120 
chemical relations of, 112 
compared with other members of 

the group, 135 
excretion of, 120 
group, 112 
Auto-oxidation, 331 

Bacteria, irritant action of, 263 
Bacterial toxins, 260 
action of, 261 
irritant, 263 

production of antitoxins, 266 
type of, 266 
characteristics of, 265 
historical, 260 
specificity of, 267 
Bacteriolysin, 261 
Barium chloride, action of, 174 
local, 176 

on alimentary canal, 176 
on central nervous system, 176 
on circulatory system, 174 
on heart, 174 

on peripheral arterioles, 175 
on skeletal muscle, 176 
on uro-genital muscle, 176 
salts, 314 

therapeutic indications for, 177 
Belladonna, 112; and see Atropine 
Benzaconine, 201 
Benzene, 237 
Beta-eucaine, 219 
Bismuth, ammonium citrate, 378 
and its salts, 378 

action of, 378 
subcarbonate, 378 
subcitrate, 378 
subnitrate, 378 
Bone, action of phosphorus on, 346 

composition of, 347 
Broom plant, 151 
Brucine, 96, 105 
Bufonine, 194 
Bufotaline, 194 

Cacodylic acid, 350 
Caffeine, 89 

absorption of, 94 

action of, 90, 95 



I^DEX 



389 



Caffeine, action of, diuretic, 94 • 
on cardiac mechanism, 93 
on central nervous system, 90 
on circulation, 92 
on medulla, 91 
on metabolism, 94 
on respiratory mechanism, 94 
on skeletal muscle, 91 
on spinal cord.. 91 
on vasomotor apparatus, 93 
summary of, 95 
chemical relationships of, 89 
excretion of, 94 
group, 89 
Calabar bean, 130 
Calcium carbonate, 324 
hydrate, 324 
salts, 310 

action of. in coagulation of 
blood, 311 
on heart. 311 
on metabolism, 312 
on nerve tissue, 312 
excretion of, 312 
Calomel. 371; and see Mercury, salts of 
Cantharidin, 269 ; and see Irritants 
irritant action of, 273 
type, irritants of, 273 
Cantliari- ve-icatoria, 269 
Carbolic acid, see Phenol 

ira, 278; and see Vegetable cathar- 
tics 
Cassia, 278 

i oil, 280; and see Vegetable ca- 
thartics 
Catharsis, 275 
Cathartics, see Purgatives 

table, 274; and see Vegetable 
cathartics 
Cations, 
Cephselis Ipecacuanha, 212 

Mill -IlltS. 

Chemical changes, 6 
Chloral hydrai 

action of. 63. 8 l 

on nervo '■ 64 

chemica I 

-;ii symptoms produced by, 64 
histories ' 
Chloroform, 50 
absorption of. 
action <>f. 50, 
..n alimentary canal, - r >"» 
r,n blood-pressure, 52 
on blood-vessels, 5 t 
on central nervous system, - r 'l 
on circulatory system, 
nn heart, 

on voluntary muscles, 55 
summary of. 57 
excretion of, 58 



Chloroform, stages of anesthesia, 50 
Choline, 129 
Cinchona, 222 

succirubra, 222 
Cinchonidine. 222; and see Quinine 
Cinchonine, 222; and see Quinine 
Citric acid, 326, 327 
Claviceps purpurea, 165 
Coal tar antipyretics, 231; and see An- 
tipyretics, coal tar 
antiseptics, 237 ; and sec Antisep- 
tic-, coal tar 
series, 231 
Cocaine. 213 

action of, 214, 220 
anesthetic, 217 
local, 217 

on central nervous system, 214 
on circulatory system, 215 
on eye, 217 
on heart, 216 

on peripheral blood-vessels, 215 
on skeletal muscle. 216 
summary of, 220 
anesthetic action of, 217 
chemical. 213 
elimination of. 217 
habit, 218 
historical. 213 
spinal analgesia by, 218 
substances which produce anes- 
thesia similar to, 219 
Codeine, action of. 79 
chemistry of, 06, 67 
retion of, 81 
Colchicein, 210 
Colchicine, 210 
action of, 210 

on white blood corpuscles, 210 

niic. 210 
toxic. 210 
chemical, 210 
historical, 210 
Colehicum autumnale, 210 
Cold, a- counter irritant. 281 
Colloids. 288, 
( olocynth, 280; and see Vegetable ca- 

thari ics 
Conhydrine, l 17 

Coniine, 136, 147; and see Nicotine 
action «>f. on autonomic oervous 
•.•in. 1 18 
on central nervous system, l » s 
on circulatory apparatus, l 19 
on heart, 149 
on motor nerve endin 
on respiratory movements, 1 19 
and sparteine group, l 17 

action of, l 17, l I s 
chemical, 147 
retion of, 150 



390 



INDEX 



Coniine, historical, 147 

methyl, 147 
Conium maculatum, 136, 147 
Convallaria, 181 
Copper acetate, 366 
and its salts, 366 
action of, 366 
disinfectant, 366 
systemic, 367 
toxic, 366 
elimination of, 366 
arsenite, 366 
sulphate, 366 
Corncockle, 195 
Cornutine, 165 

Counter irritants, 259, 282; and see 
Counter irritation 
application of, 283, 287 
list of, 287 
Counter irritation, 282 
agents used for, 287 
conditions which suppress, 286 
sites for application of, 283 
theory of, 282 
Croton oil, 281; and see Vegetable ca- 
thartics 
tiglium, 280 
Crotonoleic acid, 281 
Crystalloids, 288, 289 
Cumulative effect of drugs, 16 
Curare, 107 

absorption of, from stomach, 109 
action of, 107, 108 

on motor nerve endings, 108 
on peripheral ganglia, 109 
comparison of, with related drugs, 

110 
group, 107 
Curine, 107 
Cyanides, 197; and see Hydrocyanic 

acid 
Cyan-methemoglobin, 199 
Cyanogen, 197 
Cytisus scoparius, 151 

Delphinine, 201 

Dicacodylic acid, 350 

Digitalein, 181; and see Digitalis 

Digitaline, 181; and see Digitalis 

Digitalis, 181 

action of, 182. 183, 193 
cumulative, 192 
diuretic, 191 
irritant, 192 
local, 192 

on blood-pressure, 188 
on central nervous axis, 190 
on circulatory svstem, 183 
on heart. 183, 184, 185 
on peripheral arterioles, 187 
on respiration, 188 



Digitalis, action of, summary of, 193 
chemical, 181 
glucosides of, 181 
group, 181 
historical, 181 
Digitophylline, 181; and see Digitalis 
Digitoxin, 181; and see Digitalis 
Dissociation, 289 

Dosage, age as a factor in determin- 
ing, 7 
Fried's rule for, 9 
tables of, 380 
Young's rule for, 8 
Dose table, 380 
Drugs, action of, general, 4 
indirect, 5 
local, 4 
nature of, 3 

relation of, to chemical compo- 
sition, 6 
specific, 4 
changes induced by in body, 11 
cumulative effect of, 16 
denned, 2, 3 
excretion of, 18 
fate of, in body, 18 
methods of administering, 13 
by hypodermic injection, 14 
by inhalation, 15 
by insufflation, 15 
by intramuscular injection. 14 
by intravenous injection, 14 
by local application, 15 
by mouth, 13 
by rectum, 13 
by transfusion, 15 
pharmacologic versus therapeutic 

action of, 17 
specific, 4 
summation of, 16 
tolerance of, 17 
Duboisia Hopwoodii, 136 

myoporoides, 112 
Duboisine, 112; and see Atropine 



Ecgonine, 213 

Elaterium, 276. 280; and see Vegetable 

cathartics 
Electrolytes. 289 
Emetics, irritant, action of, 88 

peripheral acting, 88 
Emetine. 212 

action of. 212 

chemical. 212 

historical. 212 
Empirical treatment, 3 • 
Enoephalopathia satnrnalis. 362 
Endotoxins. 260. 263 
Enemas, saline cathartics as, 323 
Epinephrine, 152 



INDEX 



391 



Epinephrine, action of, 152, 153, 163 
general discussion of, 161 
on blood-pressure, 153 
on eye, 159 

on gastric movements, 158 
on glands, 158 
on heart, 157 

on intestinal movements, 158 
on mammalian body, 159 
on nervous system, 153 
on salivary glands, 158 
on uro-genital apparatus, 158 
summary of, 163 
chemical, 152 
glycosuria caused by, 161 
historical, 152 

vasoconstriction caused by, 153 
Epsom salt, see Magnesium sulphate 
Ergot, 165 

action of, 166 

chemically pure principles, 166 
extracts of ergot, 169 
on alimentary canal, 173 
on circulatory system, 171 
on eye, 173 
on heart, 172 
on nerve centers, 173 
on secreting glands, 173 
on urinary bladder, 173 
on uterus, 170 
chemical, 165 

effect of, in connection with epi- 
nephrine, 159 
gangrene following use of, 171 
historical, 165 
series, 165 
Ergotinic acid. 165 
Ergotoxine, 165; and see Ergot 

action of, 167 
Erythrophloeum, 181 
Erythroxylon coca, 213 
Eserine, 130; and see Physostigmine 
Ether, 39 

absorption of, 47 
action of, 42, 48 

on alimentary canal, 47 
on blood-pressure, 44 
on blood-vessels, 45 
on central nervous system, 42 
on circulatory system, 44 
on heart, 44 

on respiratory center, 44 
on voluntary muscle, 47 
summary of, 48 
and chloroform, relative safety of 

40 
distribution of, 17 
exsrel ion of, 47, 48 
general acl ton of, in 
stages of anesthesia, 40, 42 
Ether and chloroform group, 89 



Ethyl alcohol, 19; and see Alcohol 
Eucaine, 219 
Excretion of drugs, 18 

Frangula, 278; and see Vegetable ca- 
thartics 
Freezing point, depression of, 290 
Fried's rule for dosage, 9 

Gelsemium sempervirens, 150 

Gelsemine, 150 

Gelseminine, 150 

Glauber's salt, see Sodium sulphate 

Headache remedies, 235 
Heat as counter irritant, 287 
loss of, 225 

production of, 224, 227 
regulation of, 224, 226 
Hellebore, 206 
Helleborine, 206 

action of, on skeletal muscle, 
207 
Helleborus, 181 
Hemoglobin, 338 
Henbane, 112 
Heroin, action of, 80 
chemistry of, 67 
Holocaine, 219 
Hydrochloric acid, 326 
Hydrocyanic acid, 197 
action of, 197 

on central nervous system, 197 
on circulatory system, 199 
on heart, 199 
on metabolism, 199 
on respiration, 198 
chemical, 197 
Hydrogen peroxide, 331 
Hyoscine, 112, 121; and see Atropine 
Hyoseyamine, 112; and see Atropine - 
Hyoscyamus niger, 112 
Hypodermic injection of drugs, 14 
Hypophysis, 257 

influence of, on heart, 257 
on nerve functions, 257 
on smooth muscle, 257 
infundibulum of, 257 
Hypophysin, 257 

Ichthyol, 342 
[gnatia, 98 
[nflammation, 262 

due to irritation, 270 
[nfundibulnm of hypophysis, 267 
[nhalation of drugs. 15 
[nsufflation of drugi 
[nternal secretions, 248 

organs producing, 2 in 
[ntestines, normal movement of. 73 
[ntramuscular Injection of drugs, U 



392 



INDEX 



Intravenous injection of drugs, 14 
Ions, 289 
Ipecacuanha, 212 
Iron, 338 

astringent action of, 340 

chloride, 340 

evidence of absorption of, 339 

normal relations of, in body, 338 

-protein compounds, 339 
Irritant action, nature of, 261, 262 

of cantharidin type, 273 

of mustard series, 272 

of volatile oils, 272 
Irritants, 259 

of alimentary canal, 274 

of skin, 268 
action of, 269 
by permeability of skin, 269 
inflammatory, 270 
historical, 268 
Irritation, degrees of, 264 
Isoamylamine, 165, 166; and see Ergot 

action of, 167 
Iso-pilocarpine, 122 
Isotonic physiological solutions, 297; 
and see Solution 

Jalap, 280; and see Vegetable cathar- 
tics 
group, purgative action of, 279 

Laughing gas, see Nitrous oxide 
Lead, 357 

acetate, 357 
action of, 357 

on circulatory system, 361 
on digestive tract, 360 
on muscles, 362 
on nervous system, 361 
toxic, 357, 362 
antidote for, 359 
carbonate, 357 
chemical, 357 
chronic poisoning by, 359 
colic, 359 
excretion of, 360 
historical, 357 
iodide, 357 
monoxide, 357 
nitrate, 357 
salts of, 357 
sugar of, 357 
sulphate, 357 
toxic action of salts of, 357, 359, 

362 
white, 357 
Lecithins, 348 

Liquors, percentage of alcohol in, 20 
Lithium salts, 308 

Liver, in relation to alcohol oxidations, 
34 



Lobelia inflata, 136, 150 
Lobeline, 136, 150; and see Nicotine 
Local application of drugs, 15 
Locke's solution, 300, 302 
Lymph, as physiological solution, 301, 
302 

Magnesium salts, action of, 313 

sulphate, 321 
Malaria, action of quinine in, 223 
Mandragora autumnalis, 112 
Mandragorine, 112; and see Atropine 
Mandrake, 112 
Materia medica, defined, 2 
Mercuric chloride, 368; and see Mer- 
cury 
iodide, 368; and see Mercury 
Mercurous chloride, 368; and see Mer- 
cury 
Mercury, absorption of, 368 
albuminate of, 334 
and its salts, 368 
action of, 368 
antiseptic, 369 
on alimentary tract, 371 
on animal protoplasm, 370 
on bacteria, 369 
on circulatory system, 372 
on kidney, 372 
on respiratory system, 372 
toxic, 368, 374 
excretion of, 373 
poisoning by, 374 
toxicity of, 368, 374 
Metal albuminates, formation of, 333 
Methyl coniine, 147 
Monkshood, 201 
Morphine, and see Opium 
action of, 68, 82 

on alimentary tract, 75 
on central nervous system, 68 
on circulatory system, 70 
on eye, 78 
on frog, 78 
on heart, 70 
on intestines, 75 
on metabolism, 79 
on stomach, 75 
summary of, S2 
and opium series, 66 
chemistry of, 66, 67 
effect of, on electrocardiogram, 73 
excretion of, 80 
Mouth, administration of drugs by, 13 
Muscarine, 128 
action of, 129 

on alimentary tract, 130 
on blood-pressure, 130 
on circulatory system, 129 
on eye, 130 
on glands, 130 



IXDEX 



393 



Muscarine, action of, on heart, 129 
on skeletal muscle, 207 
compared with other members of 

the group, 135 
group, 122 
Mustard, 268; and see Irritants 

series, toxic glucosides of, 272 
Myxedema, 250 

Xarcotine, action of, 80 

chemistry of, 66 
Xicotiana tabacum, 136 
Nicotine, 136 

action of, 137 

compared with curare. 110 

on alimentary canal. 142 

on cardiac muscle, 140 

on central nervous system, 137 

on cerebral cortex, 137 

on circulatory system, 139, 140 

on eye, 142 

on glandular apparatus, 142 

on medulla, 137 

on nervous apparatus of heart, 

140 
on peripheral ganglia, 138 
on spinal cord, 138 
on vasomotor system. 142 
excretion of, 143 
general svmptoms of, 137 
habit, 143 
series, 136 
tolerance of. 145 
Xitric acid, 326 

Xitrites and nitroglycerine*. 178 
action of, 178, ISO 

on circulatory system. 178 
on heart, 179 

on respiratory apparatus, 180 
summary of, 180 
as methemoglobin formers. 180 
Nitro-glycerine, 178; and see Xitrites 
Nitroglycerines, 178 
Nitrons oxide 

art inn of. 58 

adminisi ration of, 
anesthetic eff< -. 62 

Novocaine, 220 

Xucleo-proteins, 348 

Xux vomit ■ tychnine 

Oil of mustard, 272 

of wintergreen, 232. 238; and see 
Antipyretics, coal tar 
Opium. (;•;•. and n ■<■ Morphine 

abuse of, s ! 

alkaloids 

chemistry of, 67 
Osmosis, 290, 291 
Osmotic pressure, 200. 291 
Ox'dizing agents, 329 



Oxygen, 329 

effect of increase of, 330 

Papaverine, action of, 80 

chemistry of, 66 
Parahydroxyphenylethylamine, 16 5, 
166; and see Ergot 
action of, 168 
Parathyroidectomy, results of, 250, 253 
Parathyroids, 249, 253; and see Thy- 
roid 
effect of removal of. 250, 253 
Koch's observations on, 253. 254 
relation of, to thyroids, 251 
tetany, 253 
Peroxides^ 329 
Pharmacist, defined. 2 
Pharmacognosy, defined, 2 
Pharmacologic versus therapeutic ac- 
tion of drugs, 17 
Pharmacological action, relation of, to 
chemical composition, 6 
agencies, 2 
factors, 1 
Pharmacology, defined, 1 
Pharmacy, defined. 2 
Phenol. 232. 237. 238. 239 
action of, 239, 243 
corrosive, 241 

on central nervous system, 240 
on circulatory system, 241 
on protoplasm. 239 
summary of, 243 
toxic. 239 
chemical, 237 
excretion of, 241 
historical, 237 
toxicology of, 241 
Phenol sulphuric acid. 239 
Phenolphthalein. 27!>: and see \ 

table cathartic- 
Phenols, 239 

Phosphates, in body. 3 1:; 
action of. 347 
relation of inorganic, 3 17 
iphatids, 34S 
PhoBpho-proteins, 3 
Phosphorus, 343 
ad ion of, 3 1 1 
on Bkeletal structure, 346 
poisonous, 3 1 1 
as a protoplasmic poison, 3 l 1 
compounds of. 343 
fatty degeneral i«>n due to. 3 1:> 
historical, 343 
organic compounds of, 3 I s 
poisoning, 344 
Phthaleins, 279 
Physical-chemical changt 
Physiological factors modifying phar- 
macological responses, 7 



394 



INDEX 



Physiological solutions, 297; and see 

Solution 
Pliysostigma venenosum, 135 
Physostigniine, 130 

action of, 131, 134 

on central nervous system, 133 
on circulatory apparatus, 132 
on eye, 131 

on muscles of stomach and in- 
testines, 133 
on striped muscle, 133 
summary of, 134 
compared with other members of 

the group, 135 
group, 122 
Pilocarpidine, 122 
Pilocarpine, 122 

action of, 122, 123, 128 
on alimentary tract, 126 
on blood-vessels, 126 
on central nervous system, 126 
on circulatory apparatus, 125 
on eye. 127 
on glands, 123 
on heart, 125 
on respiratory tract, 126 
summary of, 128 
compared with other members of 

the group, 135 
group, 122 

. comparison of members of, 135 
Pilocarpus jaborandi, 122 
Piperidine, 147, 150 
Pituitary gland, 255 
action of, 255 
administration of, 256 
anatomical, 255 
atrophy of, 256 
hypertrophy of, 256 
relation of, to other organs, 257 
result of removal of secretion of. 
255 
Piturine, 136; and see Nicotine 
Podophyllin. 280 ; and see Vegetable ca- 
thartics 
Poison, defined, 2 
Poison ivy, 269 

irritant action of, 273 
Potassium, carbonate, 324 

cyanide, see Hydrocyanic acid 
hydrate, 324 

salts. 305; and sec Sodium salts 
Protocurarine, 107 
Protocuridine. 107 
Protocurine, 107 
Provera trine, 206 
Prussic acid. 197; and see Hydrocyanic 

acid 
Pseudoaconitine, 201 
Ptomains, 260 
Purine, 89; and see Caffeine 



Purine, bodies, chemical relationships of, 
89 

Pustulation, 272 

Pyridine, 147, 150 

Pyrogallol, 238, 243; and see Antisep- 
tics, coal tar 

Quillaja saponaria, 195 
Quinidine, 222; and see Quinine 
Quinine, 222 

action of, 222, 230 
antipyretic, 224, 228 
on body temperature, 224 
on central nervous system, 229 
on digestion, 228 
on digestive tract, 228 
on liver, 229 
on malaria, 223 
on muscle, 228 
on undifferentiated protoplasm, 

223 
summary of, 230 
systemic, 222 
chemical, 222 
elimination of, 229 
historical, 222 
Quinoline, 222; and see Quinine 

Race and species, susceptibility due 
to, 9 

Rational treatment, 3 

Rectum, administration of drugs by, 13 

Resorcin, 238, 243 ; and see Antiseptics, 
coal tar 

Rhamnus frangula, 278 
purshiana, 278 

Rheum officinale, 278 

Rhubarb, 278; and see Vegetable ca- 
thartics 

Ricinus communis, 280 

Ringer's solution, 299, 302 

Rochelle salt, see Sodium potassium 
tartrate 

Rubidium salts, 308 

Salicylates, 244 

action of, 244, 246 
antipyretic, 246 
on alimentary canal, 245 
on central nervous system, 244 
on circulatory system, 254 
on protoplasm, 244 
summary of. 246 
toxicity of. 244 
Salicylic acid. 238. 244; and see Salicy- 
lates 
Saline cathartics. 315 
as enemas. 323 

nature of action of, 315, 318 
Salol, 238. 243; and see Antiseptics, 
coal tar 



INDEX 



395 



Salt action, 292 

principles underlying, 288 
Salts, and see Saline 

action of, 303; and see Sodium, 

Potassium, etc. 
in solution, physical and chemical 

characteristics of. 288 
of heavy metals, absorption of, 
336 
distribution of, in body, 336 
excretion of, 336 
general reaction of, 333 
Salvarsan, 350, 354, 355; and see Ar- 
senic 
Saponaria officinalis. 195 
Saponin, action of, 195, 196 
and sapotoxin group, 195 
chemical, 195 
historical, 195 
Sapotoxin, 195; and see Saponin 
Sarsaparilla, 195 
Scilla. 181; and see Digitalis 
Scopolamine, 121 

Senna, 278; and see Vegetable cathar- 
tics 
Sera, as physiological solutions, 301, 

302" 
Sex, susceptibility due to, 10 
Silver and its salts, 376 
action of. 37G 
antiseptic, 376 
local 

toxic, 376 
nitrate of. 

temic effects of, 377 
Sinalbin, 26S 

Sinapis, 208. 272; and see Irritants 
Smilax, 195 
Soapbark, 195 
Soapwort. 195 

Sodium and potassium group, 304 
arsanilate, 350. 354 
bromide. 
carbonate] 
chloride. 304 

action of. 303 
cyanide, see llydrooyanic acid 
hydrate. 324 
iodide. 305 
iiitrnto. 305 

nitrite. 17$: and see Xitri 
phosphate . 

potassium tartrate, action of. 320 
salts. 304 
sulphate. 305 
aetion of 318 
Solanin. 105. 100 
Solanum. 105 

Solutions, i^otonie physiological, 207 
Loeke's. 300, 302' 
lymph, as physiological, 301. 302 



Solutions, physiological saline, 297, 302 
perfusion of, 298 
summary of, 302 
Pdnger's, 299, 302 
sera, as physiological, 301, 302' 
Sparteine, 151 
Sphacelinic acid, 1G5 
Stomach, normal movements of, 73 
Stovaine, 219 
Strontium salts, 314 
Strophanthine, 181; and see Digitalis 
Strophantus, 181; and see Digitalis 
Strychnine, 96 

* action of, 96, 97, 106 

on alimentary canal, 104 
on brain-stem, 97 
on cardiac muscles, 101 
on circulation, 100 
on medulla, 99 
on metabolism, 104 
on respiration, 100 
on skeletal muscle, 103 
on special sense organs, 104 
on spinal cord. 97 
summary of. 106 
alkaloids of, 96 
excretion of, 105 
group, 96 
poisoning by, 105 
Strychnos nux vomica, 96, 107 
slmea, 107 
ignatia, 96 
toxifera, 107 
Sugar of lead. 357 
Sulphates, 342 
Sulphides, 341 
Sulphonal. 342 
Sulphur. 341 

compounds of, 341 
organic compounds of. 342 
Sulphuric acid. 326 
Summation. 10 
Superoxides, 331 

Suprarenal gland, srr Kpinephrine 
Suprarenin, 15:!: and see Epinephrine 
iptibility, individual. 
due i<> race and speci 
due to sox. 10 
due to weight. 1 1 

Tartaric acid, 320. 327 
Tetany, thyroid, 251 

parathyroid, 
Thebaine, loo 

aetion of, SO 
ehemistry of, 00. r,7 

Theobromine, oo : and srr Caffeine 
Theophyline, 89; and see Caffeine 
Therapeutics, defined, 2 
Thorn apple, 112 
Thyroid gland, 249 



396 



INDEX 



Thyroid gland, action- of, 250 

chemical, 249 

effect of removal of, 250 

engrafting of, 251 

historical, 249 

myxedema, 250 

relation of, to parathyroids, 251 
to pituitary gland, 257 

result of feeding, 252 

tetany, 251 
Thyroiodin, 249; and see Thyroid 
Tobacco, 136; and see Nicotine 
Tolerance of drugs, 17 
Toxicodendrol, 269, 273 
Toxicology, defined, 2 
Toxins, 263 

bacterial, 260; and see Bacterial 
toxins 
Transfusions, 15 
Tropacocaine, 214, 219 
Tropic acid, 112 
Tropine, 112, 213 
Tubocurarine, 107 
Turpentine, 268; and see Irritants 
Tyramine, 166; and see Ergot 

Uric acid, 90; and see Caffeine 

Vegetable cathartics, 274 
action of, 274, 275 
cathartic, 275, 276 
irritant, 275, 277 
anthracene group of, 277 
groups of, 274 
jalap group of, 279 
neutral oil series of, 280 
Veratrine, 201, 206 



Veratrine, action of, 206 

on lieart muscle, 208 
on nervous mechanism, 206 
on sensory mechanism, 206 
on skeletal muscle, 207 
on smooth muscle, 209 
chemical, 206 
historical, 206 
Veratrum sabadilla, 206 

viride, 206 
Vesication, 272 

Volatile oils, 268; and see Irritants 
irritant action of, 272 

Water, 294 

distilled, action of, on tissues, 294 

drinking, 295 

influence of, on kidney, 296 
on metabolism, 296 

mineral, 295 
Weight, susceptibility due to, 11 
White lead, 357 

Xanthine, 89; and see Caffeine 

Yohimbine, 220 

Young's rule for dosage, 8 

Zinc, 364 

action of, 364 

disinfectant, 364 

local, 364 

systemic, 364 

toxic, 364 
chloride, 364 
oxide, 364 
salts of, 364 
sulphate, 364 



